(4-Phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone Compounds and Their Use

ABSTRACT

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain (4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds that, inter alia, inhibit 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11β-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11β-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer&#39;s disease; etc.

RELATED APPLICATION

This application is related to U.S. provisional patent application No.61/242,825 filed 16 Sep. 2009, the contents of which are incorporatedherein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeuticcompounds. More specifically the present invention pertains to certain(4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanonecompounds that, inter alfa, inhibit 11β-hydroxysteroid dehydrogenasetype 1 (11β-HSD1). The present invention also pertains to pharmaceuticalcompositions comprising such compounds, and the use of such compoundsand compositions, both in vitro and in vivo, to inhibit11β-hydroxysteroid dehydrogenase type 1; to treat disorders that areameliorated by the inhibition of 11β-hydroxysteroid dehydrogenase type1; to treat the metabolic syndrome, which includes disorders such astype 2 diabetes and obesity, and associated disorders including insulinresistance, hypertension, lipid disorders and cardiovascular disorderssuch as ischaemic (coronary) heart disease; to treat CNS disorders suchas mild cognitive impairment and early dementia, including Alzheimer'sdisease; etc.

BACKGROUND

A number of publications are cited herein in order to more fullydescribe and disclose the invention and the state of the art to whichthe invention pertains. Each of these references is incorporated hereinby reference in its entirety into the present disclosure, to the sameextent as if each individual reference was specifically and individuallyindicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understandingthe present invention. It is not an admission that any of theinformation provided herein is prior art or relevant to the presentlyclaimed invention, or that any publication specifically or implicitlyreferenced is prior art.

Glucocorticoids (cortisol in man, corticosterone in rodents) arehormones that regulate a range of pathways involved in stress andmetabolic signalling. They are antagonists of insulin action and impairinsulin-dependent glucose uptake, increase lipolysis, and enhancehepatic gluconeogenesis. These effects are evident in Cushing'ssyndrome, which is caused by elevated circulating levels ofglucocorticoids. The features of Cushing's syndrome are diverse andreflect the tissue distribution of glucocorticoid receptors in the body.They include a cluster of metabolic (central/visceral obesity, insulinresistance, hyperglycaemia, dyslipidaemia) and cardiovascular(hypertension) abnormalities which, when observed in patients withoutCushing's syndrome, constitute the metabolic syndrome. Theseabnormalities confer a substantial risk of cardiovascular disease. Inaddition, Cushing's syndrome is associated with neuropsychiatricmanifestations including depression and cognitive impairment. Thefeatures of Cushing's syndrome are reversible upon removal of the causeof glucocorticoid excess.

It is recognised that glucocorticoid activity is controlled at thetissue level by the intracellular conversion of active cortisol andinactive cortisone by 11β-hydroxysteroid dehydrogenases (see, e.g.,Seckl et al., 2001). These enzymes exist in two distinct isoforms.11β-HSD1, which catalyses the reaction that activates cortisone, isexpressed in liver, adipose tissue, brain, skeletal muscle, vascularsmooth muscle and other organs, while, 11β-HSD2, which inactivatescortisol, is predominantly expressed in the kidney. Pharmacologicalinhibition of 11β-HSD1 in rat and man with carbenoxolone (see, e.g.,Walker et al., 1995), and transgenic knockout in mice (see, e.g.,Kotelevtsev et al., 1997), results in enhanced hepatic insulinsensitivity and reduced gluconeogenesis and glycogenolysis, suggestingthat 11β-HSD1 inhibition will be a useful treatment in type 2 diabetesand other insulin resistance syndromes. Furthermore, mice lacking11β-HSD1 possess low triglycerides, increased HDL cholesterol, andincreased apo-lipoprotein A-I levels (see, e.g., Morton et al., 2001),suggesting that inhibitors of 11β-HSD1 may be of utility in thetreatment of atherosclerosis.

The link between 11β-HSD1 and the metabolic syndrome has beenstrengthened by studies in transgenic mice and man. 11β-HSD1 knockoutmice on two different genetic backgrounds are protected from dietaryobesity (see, e.g., Morton et al., 2004), while administration ofcarbenoxolone to patients with type 2 diabetes enhances insulinsensitivity (see, e.g., Andrews et al., 2003). However, it has becomeapparent that the key tissue in which 11β-HSD1 exerts the greatestinfluence upon metabolic disease is the adipose tissue rather than theliver. Mice with transgenic overexpression of 11β-HSD1 in adipose tissue(see, e.g. Masuzaki et al., 2001) have a more profound metabolicsyndrome and obesity than mice with overexpression in liver (see, e.g.,Paterson et al., 2004). In obese humans, 11β-HSD1 activity is increasedin adipose tissue, but enzyme activity is decreased in the liver (see,e.g., Rask et al., 2001).

In the CNS, 11β-HSD1 is highly expressed in regions important forcognition such as hippocampus, frontal cortex, and cerebellum (see,e.g., Moisan et al., 1990). Elevated cortisol is associated withcognitive dysfunction, and glucocorticoids have a range of neurotoxiceffects. 11β-HSD1 knockout mice are protected against age-relatedcognitive dysfunction (see, e.g., Yau et al., 2001), whileadministration of the 11β-HSD inhibitor carbenoxolone has been shown toenhance cognitive function in elderly men and type 2 diabetics who havea selective impairment in verbal memory (see, e.g., Sandeep et al.,2004). Thus, 11β-HSD1 inhibitors are of potential therapeutic utility inthe treatment of diseases such as Alzheimer's Disease, which arecharacterised by cognitive impairment.

The isozymes of 11β-HSD are also expressed in the blood vessel wall(see, e.g., Walker et al., 1991; Christy et al., 2003). 11β-HSD1 isexpressed in vascular smooth muscle, while 11β-HSD2 is expressed inendothelial cells where it modulates endothelial-dependent vasodilation(see, e.g., Hadoke et al., 2001). 11β-HSD1 knockout mice have normalvascular function, but they exhibit enhanced angiogenesis in response toinflammation or ischaemia (see, e.g., Small et al., 2005). This offerstherapeutic potential in the treatment of myocardial infarction, sinceinhibition of 11β-HSD1 may enhance revascularisation of ischaemictissues.

Studies have shown that 11β-HSD1 affects intraocular pressure in man(see, e.g., Rauz et al., 2001). Inhibition of 11β-HSD1 may be useful inreducing intraocular pressure in the treatment of glaucoma.

Glucocorticoids are involved in the regulation of bone formation andskeletal development. Treatment of healthy volunteers with carbenoxoloneled to a decrease in bone resorption markers suggesting that 11β-HSD1plays a role in bone resorption (see, e.g., Cooper et al., 2000).11β-HSD1 inhibitors could be used as protective agents in the treatmentof osteoporosis.

Certain compounds that inhibit 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1) that are useful in the treatment, control, and/or preventionof disorders (e.g., diseases) that are responsive to the inhibition of11β-HSD1 are described in international (PCT) patent application numberPCT/GB2009/000686 filed 13 Mar. 2009 (published as WO 2009/112845 A1 on17 Sep. 2009).

Certain compounds of the following formula which allegedly inhibit11β-HSD1, and allegedly are useful in the treatment and prevention ofdiseases such as metabolic diseases, in particular, diabetes type 2,obesity, and dyslipidemia, are described in WO 2010/023161 A1 (publishedon 4 Mar. 2010).

The inventors have discovered an especially preferred class ofcompounds, which inhibit 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1), and which additionally have improved pharmacokinetic and/ormicrosomal stability properties, and which are useful in the treatment,control, and/or prevention of disorders (e.g., diseases) that areresponsive to the inhibition of 11β-HSD1.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certain(4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanonecompounds (referred to herein as PPPT compounds), as described herein.

Another aspect of the invention pertains to a composition (e.g., apharmaceutical composition) comprising a PPPT compound, as describedherein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to a method of preparing acomposition (e.g., a pharmaceutical composition) comprising the step ofadmixing a PPPT compound, as described herein, and a pharmaceuticallyacceptable carrier or diluent.

Another aspect of the present invention pertains to a method ofinhibiting 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) function(e.g., in a cell), in vitro or in vivo, comprising contacting the cellwith an effective amount of a PPPT compound, as described herein.

Another aspect of the present invention pertains to a method oftreatment comprising administering to a subject in need of treatment atherapeutically-effective amount of a PPPT compound, as describedherein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to a PPPT compound asdescribed herein for use in a method of treatment of the human or animalbody by therapy.

Another aspect of the present invention pertains to use of a PPPTcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the treatment is treatment or prevention of adisorder (e.g., a disease) that is ameliorated by the inhibition of11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).

In one embodiment, the treatment is treatment or prevention of metabolicsyndrome, which includes conditions such as type 2 diabetes and obesity,and associated disorders including insulin resistance, hypertension,lipid disorders and cardiovascular disorders such as ischaemic(coronary) heart disease.

In one embodiment, the treatment is treatment or prevention of a CNSdisorder (e.g., a CNS disease) such as mild cognitive impairment andearly dementia, including Alzheimer's disease.

Another aspect of the present invention pertains to a kit comprising

(a) a PPPT compound, as described herein, preferably provided as apharmaceutical composition and in a suitable container and/or withsuitable packaging; and(b) instructions for use, for example, written instructions on how toadminister the compound.

Another aspect of the present invention pertains to a PPPT compoundobtainable by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to a PPPT compoundobtained by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION Compounds

One aspect of the present invention relates to certain(4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanonecompounds (for convenience, collectively referred to herein as “PPPTcompounds”), which are related to the following compound:

(4-Phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone

Some embodiments of the invention include the following:

(1) A compound selected from compounds of the following formula, andpharmaceutically acceptable salts, hydrates, and solvates thereof:

wherein:

-   -   —W is independently —H or —Y;    -   —Y is independently —Y¹, —Y², —Y³, —Y⁴, or —Y⁵;    -   —Y¹ is independently —OH;    -   —Y² is independently —Y^(2A), —Y^(2B), or —Y^(2C);    -   —Y³ is independently —Y^(3A), —Y^(3B), or —Y^(3C);    -   —Y⁴ is independently —F, —Cl, —Br, or —I;    -   —Y⁵ is independently —CN;        wherein:    -   —Y^(2A) is independently —OR^(YA);    -   —Y^(2B) is independently —OR^(YB);    -   —Y^(2C) is independently —OR^(YC);    -   —Y^(3A) is independently —R^(YA);    -   —Y^(3B) is independently —R^(YB);    -   —Y^(3C) is independently —R^(YC);        wherein:    -   each —R^(YA) is independently saturated aliphatic C₁₋₆alkyl;    -   each —R^(YB) is independently saturated aliphatic        halo-C₁₋₆alkyl;    -   each —R^(YC) is independently saturated aliphatic        hydroxy-C₁₋₆alkyl;        and wherein:    -   each of -J¹, -J², -J³, and -J⁴ is —H;    -   or each of -J² and -J⁴ is —H; and -J¹ and -J³ taken together        form —CH₂— or —CH₂CH₂—;    -   or each of -J¹ and -J³ is —H; and -J² and -J⁴ taken together        form —CH₂— or —CH₂CH₂—;    -   or each of -J² and -J³ is —H; and -J¹ and -J⁴ taken together        form —CH₂— or —CH₂CH₂—;        and wherein:    -   —R^(N) is independently —H or —R^(NN);    -   —R^(NN) is independently saturated aliphatic C₁₋₆alkyl;        and wherein:    -   —R^(B1) is independently —H or —R^(BB);    -   —R^(B2) is independently —H or —R^(BB);        wherein:    -   each —R^(BB) is independently —R^(BB1), —R^(BB2), or —R^(BB3);        wherein:    -   each —R^(BB1) is independently saturated aliphatic C₁₋₆alkyl,        and is optionally substituted with one or more substituents        selected from —F, —OH, —OR^(BBB), —OCH₂F, —OCHF₂, —OCF₃, —NH₂,        —NHR^(BBB), and —NR^(BBB) ₂; wherein each —R^(BBB) is        independently saturated aliphatic C₁₋₄alkyl;    -   each —R^(BB2) is independently —F, —Cl, —Br, or —I;    -   each —R^(BB3) is independently —CN;        and wherein:    -   n is independently 0, 1, 2, 3, 4, or 5;    -   each —R^(F) is independently —R^(Z), —F, —Cl, —Br, —I, —CF₃,        —OH, —OR², —OCF₃, —SR², —S(═O)₂R^(Z), or —CN; and    -   each —R^(Z) is independently saturated aliphatic C₁₋₆alkyl, and        is optionally substituted with one or more substituents selected        from —F, —Cl, —OH, —OR^(ZZ), —OCH₂F, —OCHF₂, and —OCF₃; wherein        each —R^(ZZ) is independently saturated aliphatic C₁₋₄alkyl;    -   with the proviso that the compound is not        (4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone        or a pharmaceutically acceptable salt, hydrate, or solvate        thereof.

For the avoidance of doubt, it is not intended that the pyrazole ring(shown on the far left of the above formula) is fused to any otherrings. For example, it is not intended that —R^(N) and —R^(B2), togetherwith the atoms to which they are attached, form a ring.

The Proviso

For convenience, the compound(4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone,which is the subject of the proviso, is shown below. It appears asCompound EE-60 at page 59 of WO 2009/112845 A1.

(4-phenyl-piperidin-1-yl)-[5- (1H-pyrazol-4-yl)-thiophen-3-yl]-methanone CAS Registry No. 1187467-46-4

The Group —W

(2) A compound according to (1), wherein —W is independently —Y.

(3) A compound according to (1), wherein —W is independently —H.

The Group —Y

(4) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y¹, —Y², —Y³, or —Y⁴.

(5) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y¹, Y², or Y³ _(.)

(6) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y¹ or —Y².

(7) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y¹.

(8) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y².

(9) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y³.

(10) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y⁴.

(11) A compound according to any one of (1) to (3), wherein —Y, ifpresent, is independently —Y⁵.

The Group —Y²

(12) A compound according to any one of (1) to (11), wherein —Y², ifpresent, is independently —Y^(2A) or —Y²⁸.

(13) A compound according to any one of (1) to (11), wherein —Y², ifpresent, is independently —Y^(2A).

(14) A compound according to any one of (1) to (11), wherein —Y², ifpresent, is independently —Y^(2B).

(15) A compound according to any one of (1) to (11), wherein —Y², ifpresent, is independently —Y^(2C).

The Group —Y³

(16) A compound according to any one of (1) to (15), wherein —Y³, ifpresent, is independently —Y^(3A) or —Y^(3A).

(17) A compound according to any one of (1) to (15), wherein —Y³, ifpresent, is independently —Y^(3A).

(18) A compound according to any one of (1) to (15), wherein —Y³, ifpresent, is independently —Y^(3B).

(19) A compound according to any one of (1) to (15), wherein —Y³, ifpresent, is independently —Y^(3C).

The Group —Y⁴

(20) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —F, —Cl, or —Br.

(21) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —F or —Cl.

(22) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —F.

(23) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —Cl.

(24) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —Br.

(25) A compound according to any one of (1) to (19), wherein —Y⁴, ifpresent, is independently —I.

The Group —R^(YA)

(26) A compound according to any one of (1) to (25), wherein each—R^(YA), if present, is independently saturated aliphatic C₁₋₄alkyl.

(27) A compound according to any one of (1) to (25), wherein each—R^(YA), if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu,or -tBu.

(28) A compound according to any one of (1) to (25), wherein each—R^(YA), if present, is independently -Me, -Et, -nPr, or -iPr.

(29) A compound according to any one of (1) to (25), wherein each—R^(YA), if present, is independently -Me or -Et.

(30) A compound according to any one of (1) to (25), wherein each—R^(YA), if present, is independently -Me.

The Group —R^(YB)

(31) A compound according to any one of (1) to (30), wherein each—R^(YB), if present, is independently saturated aliphatichalo-C₁₋₄alkyl.

(32) A compound according to any one of (1) to (30), wherein each—R^(YB), if present, is independently —CF₃, —CHF₂, —CH₂F, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, or —CF₂CF₃.

(33) A compound according to any one of (1) to (30), wherein each—R^(YB), if present, is independently —CF₃, —CHF₂, —CH₂F, or —CH₂CF₃.

(34) A compound according to any one of (1) to (30), wherein each—R^(YB), if present, is independently —CF₃ or —CHF₂.

(35) A compound according to any one of (1) to (30), wherein each—R^(YB), if present, is independently —CF₃.

The Group —R^(YC)

(36) A compound according to any one of (1) to (35), wherein each—R^(YC), if present, is independently saturated aliphatichydroxy-C₁₋₄alkyl.

(37) A compound according to any one of (1) to (35), wherein each—R^(YC), if present, is independently —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)₂OH, or —CH₂CH₂CH₂CH₂OH.

(38) A compound according to any one of (1) to (35), wherein each—R_(YC), if present, is independently —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,or —CH₂CH₂CH₂CH₂OH.

(39) A compound according to any one of (1) to (35), wherein each—R^(YC), if present, is independently —CH₂OH, —CH₂CH₂OH or —CH₂CH₂CH₂OH.

(40) A compound according to any one of (1) to (35), wherein each—R^(YC), if present, is independently —CH₂OH.

The Group -J-

(41) A compound according to any one of (1) to (40), wherein each of-J¹, -J², -J³, and -J⁴ is —H.

(42) A compound according to any one of (1) to (40), wherein each of -J²and -J⁴ is —H; and -J¹ and -J³ taken together form —CH₂— or —CH₂CH₂—.

(43) A compound according to any one of (1) to (40), wherein each of -J²and -J⁴ is —H; and -J¹ and -J³ taken together form —CH₂—.

(44) A compound according to any one of (1) to (40), wherein each of -J²and -J⁴ is —H; and -J¹ and -J³ taken together form —CH₂CH₂—.

(45) A compound according to any one of (1) to (40), wherein each of -J¹and -J³ is —H; and -J² and -J⁴ taken together form —CH₂— or —CH₂CH₂—.

(46) A compound according to any one of (1) to (40), wherein each of -J¹and -J³ is —H; and -J² and -J⁴ taken together form —CH₂—.

(47) A compound according to any one of (1) to (40), wherein each of -J¹and -J³ is —H; and -J² and -J⁴ taken together form —CH₂CH₂—.

(48) A compound according to any one of (1) to (40), wherein each of -J²and -J³ is —H; and -J¹ and -J⁴ taken together form —CH₂— or —CH₂CH₂—.

(49) A compound according to any one of (1) to (40), wherein each of -J²and -J³ is —H; and -J¹ and -J⁴ taken together form —CH₂—.

(50) A compound according to any one of (1) to (40), wherein each of -J²and -J³ is —H; and -J¹ and -J⁴ taken together form —CH₂CH₂—.

The Group —R^(N)

(51) A compound according to any one of (1) to (50), wherein —R^(N) isindependently —H.

(52) A compound according to any one of (1) to (50), wherein —R^(N) isindependently —R^(NN).

The Group —R^(NN)

(53) A compound according to any one of (1) to (52), wherein —R^(NN), ifpresent, is independently saturated aliphatic C₁₋₄alkyl.

(54) A compound according to any one of (1) to (52), wherein —R^(NN), ifpresent, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(55) A compound according to any one of (1) to (52), wherein —R^(NN), ifpresent, is independently -Me or -Et.

The Groups —R^(B1) and —R^(B2)

(56) A compound according to any one of (1) to (55), wherein:

-   -   —R^(B1) is independently —H or —R^(BB); and    -   —R^(B2) is independently —H.

(57) A compound according to any one of (1) to (55), wherein:

-   -   —R^(B1) is independently —H; and    -   —R^(B2) is independently —H or —R^(BB).

(58) A compound according to any one of (1) to (55), wherein:

-   -   —R^(B1) is independently —H; and —R^(B2) is independently —H.

(59) A compound according to any one of (1) to (55), wherein:

—R^(B1) is independently —R^(BB); and —R^(B2) is independently —R^(BB).

The Group —R^(B8)

(60) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB1) or —R^(BB2).

(61) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB1) or —R^(BB3).

(62) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB2) or —R^(BB).

(63) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB).

(64) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB2).

(65) A compound according to any one of (1) to (59), wherein each—R^(BB), if present, is independently —R^(BB3).

The Group —R^(BB1)

(66) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently saturated aliphatic C₁₋₄alkyl,and is optionally substituted with one or more substituents selectedfrom —F, —OH, —OR^(BBB), —OCH₂F, —OCHF₂, —OCF₃, —NH₂, —NHR^(BBB), and—NR^(BBB) ₂.

(67) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently saturated aliphatic C₁₋₄alkyl,and is optionally substituted with one or more substituents selectedfrom —F, —OH, —OR^(BBB), —OCH₂F, —OCHF₂, and —OCF₃.

(68) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently saturated aliphatic C₁₋₄alkyl,and is optionally substituted with one or more substituents selectedfrom —F, —OH, and —OR^(BBB).

(69) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently unsubstituted saturated aliphaticC₁₋₄alkyl.

(70) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu,or -tBu.

(71) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently -Me or -Et.

(72) A compound according to any one of (1) to (65), wherein each—R^(BB1), if present, is independently -Me.

The Group —R^(BB2)

(73) A compound according to any one of (1) to (72), wherein each—R^(BB2), if present, is independently —F, —Cl, or —Br.

(74) A compound according to any one of (1) to (72), wherein each—R^(BB2), if present, is independently —F or —Cl.

(75) A compound according to any one of (1) to (72), wherein each—R^(BB2), if present, is independently —F.

(76) A compound according to any one of (1) to (72), wherein each—R^(BB2), if present, is independently —Cl.

The Group —R^(BBB)

(77) A compound according to any one of (1) to (76), wherein each—R^(BBB), if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu,or -tBu.

(78) A compound according to any one of (1) to (76), wherein each—R^(BBB), if present, is independently -Me or -Et.

The Index n

(79) A compound according to any one of (1) to (78), wherein n isindependently 0, 1, 2, or 3.

(80) A compound according to any one of (1) to (78), wherein n isindependently 0, 1, or 2.

(81) A compound according to any one of (1) to (78), wherein n isindependently 0 or 1.

(82) A compound according to any one of (1) to (78), wherein n isindependently 0.

(83) A compound according to any one of (1) to (78), wherein n isindependently 1, 2, or 3.

(84) A compound according to any one of (1) to (78), wherein n isindependently 1 or 2.

(85) A compound according to any one of (1) to (78), wherein n isindependently 1,

(86) A compound according to any one of (1) to (78), wherein n isindependently 2.

(87) A compound according to any one of (1) to (78), wherein n isindependently 3.

(88) A compound according to any one of (1) to (78), wherein n isindependently 4,

(89) A compound according to any one of (1) to (78), wherein n isindependently 5.

The Group —R^(F)

(90) A compound according to any one of (1) to (89), wherein each—R^(F), if present, is independently —R^(Z), —F, —Cl, —Br, —I, —CF₃,—OH, —OR^(Z), —OCF₃, —SR^(Z), —S(═O)₂R^(Z), or —CN.

(91) A compound according to any one of (1) to (89), wherein each—R^(F), if present, is independently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt,—CF₃, —OCF₃, or —CN.

(92) A compound according to any one of (1) to (89), wherein each—R^(F), if present, is independently —F, —Cl, —CF₃, —OMe, or —CN.

(93) A compound according to any one of (1) to (89), wherein each—R^(F), if present, is independently —F, —Cl, or —CF₃.

The Group —R^(Z)

(94) A compound according to any one of (1) to (93), wherein each—R^(Z), if present, is independently saturated aliphatic C₁₋₄alkyl, andis optionally substituted with one or more substituents selected from—F, —Cl, —OH, —OR^(ZZ), —OCH₂F, —OCHF₂, and —OCF₃.

(95) A compound according to any one of (1) to (93), wherein each—R^(Z), if present, is independently saturated aliphatic C₁₋₄alkyl, andis optionally substituted with one or more substituents selected from—F, —Cl, —OH, and —OR^(ZZ).

(96) A compound according to any one of (1) to (93), wherein each—R^(Z), if present, is independently unsubstituted saturated aliphaticC₁₋₄alkyl.

(97) A compound according to any one of (1) to (93), wherein each—R^(Z), if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu,or -tBu.

(98) A compound according to any one of (1) to (93), wherein each—R^(Z), if present, is independently -Me or -Et.

The Group —R^(ZZ)

(99) A compound according to any one of (1) to (90), (94), and (95),wherein each —R^(ZZ), if present, is independently -Me, -Et, -nPr, -iPr,-nBu, -iBu, or -tBu.

(100) A compound according to any one of (1) to (90), (94), and (95),wherein each —R^(ZZ), if present, is independently -Me or -Et.

Some Preferred Substituted Phenyl Groups

(101) A compound according to any one of (1) to (78), wherein the group:

is:

wherein:

-   -   each —R^(F) is independently —R^(Z), —F, —Cl, —Br, —I, —CF₃,        —OH, —OR^(Z), —OCF₃, —SR^(Z), —S(═O)₂R^(Z), or —CN; and    -   each —R^(Z) is independently saturated aliphatic C₁₋₄alkyl, and        is optionally substituted with one or more substituents selected        from —F, —Cl, —OH, —OR^(ZZ), —OCH₂F, —OCHF₂, and —OCF₃; wherein        each —Ru is independently saturated aliphatic C₁₋₄alkyl.

(102) A compound according to (101), wherein each —R^(F), if present, isindependently —R^(Z), —F, —Cl, —Br, —I, —CF₃, —OH, —OR^(Z), —OCF₃, or—CN.

(103) A compound according to (101), wherein each —R^(F), if present, isindependently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.

(104) A compound according to (101), wherein each —R^(F), if present, isindependently —F, —Cl, —CF₃, —OMe, or —CN.

(105) A compound according to (101), wherein each —R^(F), if present, isindependently —F, —Cl, or —CF₃.

(106) A compound according to (101), wherein each —R^(F), if present, isindependently —F, —Cl, or -Me.

(107) A compound according to (101) or (102), wherein each —R^(Z), ifpresent, is independently saturated aliphatic C₁₋₄alkyl, and isoptionally substituted with one or more substituents selected from —F,—Cl, —OH, —OR^(ZZ), —OCH₂F, —OCHF₂, and —OCF₃.

(108) A compound according to (101) or (102), wherein each —R^(Z), ifpresent, is independently saturated aliphatic C₁₋₄alkyl, and isoptionally substituted with one or more substituents selected from —F,—OH, and —OR^(ZZ).

(109) A compound according to (101) or (102), wherein each —R^(Z), ifpresent, is independently unsubstituted saturated aliphatic C₁₋₄alkyl.

(110) A compound according to (101) or (102), wherein each —R^(Z), ifpresent, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(111) A compound according to (101) or (102), wherein each —R^(Z), ifpresent, is independently -Me or -Et.

(112) A compound according to any one of (101), (102), (107), and (108),wherein each —Ru, if present, is independently -Me, -Et, -nPr, -iPr,-nBu, -iBu, or -tBu.

(113) A compound according to any one of (101), (102), (107), and (108),wherein each —R^(ZZ), if present, is independently -Me or -Et.

Molecular Weight

(114) A compound according to any one of (1) to (113), wherein has amolecular weight of from 337 to 1200.

(115) A compound according to (114), wherein the bottom of the range is350, 360, 375, 400, or 425.

(116) A compound according to (114) or (115), wherein the top of therange is 1100, 1000, 900, 800, 700, 600, 500, or 450.

(117) A compound according to any one of (1) to (113), wherein thecompound has a molecular weight of from 350 to 450.

Examples of Some Specific Embodiments

(118) A compound according to (1), selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Synthesis No. Structure AA-01  1

AA-02  1

AA-03  1

AA-04  1

AA-05  1

AA-06  1

AA-07  1

AA-08  1

AA-09  1

AA-10  1

AA-11  1

AA-12  1

AA-13  1

AA-14  1

AA-15  1

AA-16  1

AA-17  1

AA-18  1

AA-19  1

AA-20  1

AA-21  1

AA-22  1

AA-23  1

AA-24  1

AA-25  1

AA-26  1

AA-27  1

AA-28  1

AA-29  1

AA-30  1

AA-31  1

AA-32  1

AA-33  1

AA-34  1

AA-35  1

AA-36  1

AA-37  1

AA-38  1

AA-39 43

AA-40  1

AA-41  1

(119) A compound according to (1), selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Synthesis No. Structure BB-01 1

BB-02 1

BB-03 1

BB-04 1

BB-05 1

BB-06 1

BB-07 1

BB-08 1

BB-09 1

BB-10 1

BB-11 1

BB-12 1

BB-13 1

BB-14 1

BB-15 1

Combinations

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,—W, —Y, Y¹, —Y², —Y³, —Y⁴, —Y⁵, —Y^(2A), —Y^(2B), —Y^(2C), —Y^(3A),—Y^(3B), —Y^(3C), —R^(YA), —R^(YB), —R^(YC), -J¹, -J², -J³, -J⁴, —R^(N),—R^(NN), —R^(B1), —R^(B2), —R^(BB), —R^(BB1), —R^(BB2), —R^(BB3),—R^(BBB), n, —R^(F), —R^(Z), —R^(ZZ), etc.) are specifically embraced bythe present invention and are disclosed herein just as if each and everycombination was individually and explicitly disclosed, to the extentthat such combinations embrace compounds that are stable compounds(i.e., compounds that can be isolated, characterised, and tested forbiological activity). In addition, all sub-combinations of the chemicalgroups listed in the embodiments describing such variables are alsospecifically embraced by the present invention and are disclosed hereinjust as if each and every such sub-combination of chemical groups wasindividually and explicitly disclosed herein.

Substantially Purified Forms

One aspect of the present invention pertains to PPPT compounds, asdescribed herein, in substantially purified form and/or in a formsubstantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% byweight, e.g., at least 60% by weight, e.g., at least 70% by weight,e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., atleast 95% by weight, e.g., at least 97% by weight, e.g., at least 98% byweight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compoundin any stereoisomeric or enantiomeric form. For example, in oneembodiment, the substantially purified form refers to a mixture ofstereoisomers, i.e., purified with respect to other compounds. In oneembodiment, the substantially purified form refers to one stereoisomer,e.g., optically pure stereoisomer. In one embodiment, the substantiallypurified form refers to a mixture of enantiomers. In one embodiment, thesubstantially purified form refers to an equimolar mixture ofenantiomers (i.e., a racemic mixture, a racemate). In one embodiment,the substantially purified form refers to one enantiomer, e.g.,optically pure enantiomer.

In one embodiment, the contaminants represent no more than 50% byweight, e.g., no more than 40% by weight, e.g., no more than 30% byweight, e.g., no more than 20% by weight, e.g., no more than 10% byweight, e.g., no more than 5% by weight, e.g., no more than 3% byweight, e.g., no more than 2% by weight, e.g., no more than 1% byweight.

Unless specified, the contaminants refer to other compounds, that is,other than stereoisomers or enantiomers. In one embodiment, thecontaminants refer to other compounds and other stereoisomers. In oneembodiment, the contaminants refer to other compounds and the otherenantiomer.

In one embodiment, the substantially purified form is at least 60%optically pure (i.e., 60% of the compound, on a molar basis, is thedesired stereoisomer or enantiomer, and 40% is the undesiredstereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., atleast 80% optically pure, e.g., at least 90% optically pure, e.g., atleast 95% optically pure, e.g., at least 97% optically pure, e.g., atleast 98% optically pure, e.g., at least 99% optically pure.

Isomers

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including mixtures (e.g., racemicmixtures) thereof. Methods for the preparation (e.g., asymmetricsynthesis) and separation (e.g., fractional crystallisation andchromatographic means) of such isomeric forms are either known in theart or are readily obtained by adapting the methods taught herein, orknown methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO), then a salt may be formed witha suitable cation. Examples of suitable inorganic cations include, butare not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺,NHR₃ ⁺, NR₄ ⁺).

Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the compound. The term “solvate” is used hereinin the conventional sense to refer to a complex of solute (e.g.,compound, salt of compound) and solvent. If the solvent is water, thesolvate may be conveniently referred to as a hydrate, for example, amono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound alsoincludes solvate and hydrate forms thereof.

Chemically Protected Forms

It may be convenient or desirable to prepare, purify, and/or handle thecompound in a chemically protected form. The term “chemically protectedform” is used herein in the conventional chemical sense and pertains toa compound in which one or more reactive functional groups are protectedfrom undesirable chemical reactions under specified conditions (e.g.,pH, temperature, radiation, solvent, and the like). In practice, wellknown chemical methods are employed to reversibly render unreactive afunctional group, which otherwise would be reactive, under specifiedconditions. In a chemically protected form, one or more reactivefunctional groups are in the form of a protected or protecting group(also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley andSons, 2006).

A wide variety of such “protecting,” “blocking,” or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R^(2C)(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyl amide (—NHCH₂C₆H₅); a benzyloxy amide(—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxy amide (—NHCO—OC(CH₃)₃,—NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH₃)₂C₆H₄C₆H₅,—NH-Bpoc), as a 9-fluorenylmethoxy amide (—NH-Fmoc), as a6-nitroveratryloxy amide (—NH-Nvoc), as a 2-trimethylsilylethyloxy amide(—NH-Teoc), as a 2,2,2-trichloroethyloxy amide (—NH-Troc), as anallyloxy amide (—NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide(—NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxideradical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: a C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle thecompound in the form of a prodrug. The term “prodrug,” as used herein,pertains to a compound which, when metabolised (e.g., in vivo), yieldsthe desired active compound. Typically, the prodrug is inactive, or lessactive than the desired active compound, but may provide advantageoushandling, administration, or metabolic properties.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Chemical Synthesis

Several methods for the chemical synthesis of PPPT compounds of thepresent invention are described herein. These and/or other well knownmethods may be modified and/or adapted in known ways in order tofacilitate the synthesis of additional compounds within the scope of thepresent invention.

Compositions

One aspect of the present invention pertains to a composition (e.g., apharmaceutical composition) comprising a PPPT compound, as describedherein, and a pharmaceutically acceptable carrier, diluent, orexcipient.

Another aspect of the present invention pertains to a method ofpreparing a composition (e.g., a pharmaceutical composition) comprisingadmixing a PPPT compound, as described herein, and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Uses

The PPPT compounds, as described herein, are useful, for example, in thetreatment of disorders (e.g., diseases) that are ameliorated by theinhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), asdescribed herein.

Use in Methods of Inhibiting 110-Hydroxysteroid Dehydrogenase Type 1(11β-HSD1)

One aspect of the present invention pertains to a method of inhibiting11β-hydroxysteroid dehydrogenase type 1 in a cell, in vitro or in vivo,comprising contacting the cell with an effective amount of a PPPTcompound, as described herein.

Suitable assays for determining 11β-hydroxysteroid dehydrogenase type 1inhibition are described herein and/or are known in the art.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo.

In one embodiment, the PPPT compound is provided in the form of apharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, adipose,lung, gastrointestinal (including, e.g., bowel, colon), breast(mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder,pancreas, brain, and skin.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound inhibits 11β-hydroxysteroid dehydrogenasetype 1. For example, suitable assays are described herein.

For example, a sample of cells may be grown in vitro and a compoundbrought into contact with said cells, and the effect of the compound onthose cells observed. As an example of “effect,” the morphologicalstatus of the cells (e.g., alive or dead, etc.) may be determined. Wherethe compound is found to exert an influence on the cells, this may beused as a prognostic or diagnostic marker of the efficacy of thecompound in methods of treating a patient carrying cells of the samecellular type.

Use in Methods of Therapy

Another aspect of the present invention pertains to a PPPT compound, asdescribed herein, for use in a method of treatment of the human oranimal body by therapy.

Use in the Manufacture of Medicaments

Another aspect of the present invention pertains to use of a PPPTcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the medicament comprises the PPPT compound.

Methods of Treatment

Another aspect of the present invention pertains to a method oftreatment comprising administering to a patient in need of treatment atherapeutically effective amount of a PPPT compound, as describedherein, preferably in the form of a pharmaceutical composition.

Disorders Treated—Disorders Ameliorated by the Inhibition of11β-Hydroxysteroid Dehydrogenase Type 1

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of a disorder (e.g., a disease) that isameliorated by the inhibition of 11β-hydroxysteroid dehydrogenase type1.

Disorders Treated—Disorders Characterised by Up-Regulation of 11β-HSD1etc.

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of a disorder (e.g., a disease) that ischaracterised by one or more of: up-regulation of 11β-HSD1;up-regulation of glucocorticoid receptor mediated pathways; elevatedPEPCK levels; other biochemical markers pertaining to glucocorticoidexcess and insulin resistance.

Disorders Treated

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of one or more of the following:

(1) Cushing's syndrome;(2) type 2 diabetes and impaired glucose tolerance;(3) insulin resistance syndromes such as myotonic dystrophy, PraderWilli, lipodystrophies, polycystic ovary syndrome, gastrointestinaldiabetes, etc.;(4) obesity and being overweight;(5) lipid disorders including dyslipidaemia;(6) atherosclerosis and its sequelae, including myocardial infarctionand peripheral vascular disease;

(7) Metabolic Syndrome;

(8) steatohepatitis/fatty liver and non-alcoholic fatty liver disease;(9) cognitive impairment in type 2 diabetes, glucose intolerance andageing, and in psychotic disorders and pre-schizophrenia;(10) dementias such as Alzheimer's disease, multi-infarct dementia,dementia with Lewy bodies, fronto-temporal dementia (including Pick'sdisease), progressive supranuclear palsy, Korsakoffs syndrome,Binswanger's disease, HIV-associated dementia, Creutzfeldt-Jakob disease(CJD), multiple sclerosis, motor neurone disease, Parkinson's disease,Huntington's disease, Niemann-Pick disease type C, normal pressurehydrocephalus, and Down's syndrome;(11) mild cognitive impairment (cognitive impairment, no dementia);(12) β-cell dysfunction in pancreatic disease;(13) glaucoma;(14) anxiety;(15) depression and other affective disorders; typical (melancholic) andatypical depression; dysthymia; post-partum depression; bipolaraffective disorder; drug-induced affective disorders; anxiety;posttraumatic stress disorder; panic; phobias;(16) delirium and acute confusional state;(17) inflammatory disease;(18) osteoporosis;(19) myocardial infarction, for example, to prevent left ventriculardysfunction after myocardial infarction; and(20) stroke, for example, to limit ischaemic neuronal loss aftercardiovascular accident.

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of one or more of the following:

(1) hyperglycaemia;(2) glucose intolerance and impaired glucose tolerance;(3) insulin resistance;(4) hyperlipidaemia;(5) hypertriglyceridaemia;(6) hypercholesterolaemia;(7) low HDL levels;(8) high LDL levels;(9) vascular restenosis;(10) abdominal obesity;(11) neurodegenerative disease;(12) retinopathy;(13) neuropathy;(14) hypertension; and(15) other diseases where insulin resistance is a component.

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of an adverse effect of glucocorticoids used totreat inflammatory diseases, such as asthma, chronic obstructivepulmonary disease, skin diseases, rheumatoid arthritis and otherarthropathies, inflammatory bowel disease, and giant cellarthritis/polymyalgia rheumatica.

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of metabolic syndrome, which includes disorderssuch as type 2 diabetes and obesity, and associated disorders includinginsulin resistance, hypertension, lipid disorders and cardiovasculardisorders such as ischaemic (coronary) heart disease.

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment or prevention of a CNS disorder (e.g., a CNS disease) such asmild cognitive impairment and early dementia, including Alzheimer'sdisease.

Treatment

The term “treatment,” as used herein in the context of treating adisorder, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the disorder, and includes a reduction in the rate ofprogress, a halt in the rate of progress, alleviation of symptoms of thedisorder, amelioration of the disorder, and cure of the disorder.Treatment as a prophylactic measure (i.e., prophylaxis) is alsoincluded. For example, use with patients who have not yet developed thedisorder, but who are at risk of developing the disorder, is encompassedby the term “treatment.”

For example, treatment includes the prophylaxis of metabolic syndrome,reducing the incidence of metabolic syndrome, alleviating the symptomsof metabolic syndrome, etc.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of a compound, or a material, composition or dosage formcomprising a compound, which is effective for producing some desiredtherapeutic effect, commensurate with a reasonable benefit/risk ratio,when administered in accordance with a desired treatment regimen.

Combination Therapies

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. For example, the compounds describedherein may also be used in combination therapies, e.g., in conjunctionwith other agents. Examples of treatments and therapies include, but arenot limited to, chemotherapy (the administration of active agents,including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs(e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery;radiation therapy; photodynamic therapy; gene therapy; and controlleddiets.

One aspect of the present invention pertains to a compound as describedherein, in combination with one or more (e.g., 1, 2, 3, 4, etc.)additional therapeutic agents, as described below.

The particular combination would be at the discretion of the physicianwho would select dosages using his common general knowledge and dosingregimens known to a skilled practitioner.

The agents (i.e., the compound described herein, plus one or more otheragents) may be administered simultaneously or sequentially, and may beadministered in individually varying dose schedules and via differentroutes. For example, when administered sequentially, the agents can beadministered at closely spaced intervals (e.g., over a period of 5-10minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart,or even longer periods apart where required), the precise dosage regimenbeing commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more otheragents) may be formulated together in a single dosage form, oralternatively, the individual agents may be formulated separately andpresented together in the form of a kit, optionally with instructionsfor their use.

Examples of additional agents/therapies that may beco-administered/combined with treatment with the PPPT compoundsdescribed herein include the following:

(1) insulin and insulin analogues;(2) insulin sensitising agents, for example: PPAR-γ agonists; PPAR-αagonists; PPAR-α/γ dual agonists; biguanides;(3) incretin-based therapies and incretin mimetics;(4) sulfonylureas and other insulin secretogogues;(5) α-glucosidase inhibitors;(6) glucagon receptor antagonists;(7) GLP-1, GLP-1 analogues, and GLP-receptor agonists;(8) GIP, GIP mimetics, and GIP receptor agonists;(9) PACAP, PACAP mimetics, and PACAP receptor δ agonists;(10) agents that suppress hepatic glucose output, such as metformin;(11) agents designed to reduce the absorption of glucose from theintestine, such as acarbose;(12) phosphotyrosine phosphatase 1B inhibitors;(13) glucose 6-phosphatase inhibitors;(14) glucokinase activators;(15) glycogen phosphorylase inhibitors;(16) fructose 1,6-biphosphatase inhibitors;(17) SIRT1 activators;(18) SGLT2 inhibitors;(19) glutamine:fructose-6-phosphate amidotransferase inhibitors;(20) anti-obesity agents, including: orilistat, pramlintide,sibutramine, fenfluramine, phentermine, dexfenfluramine, cannabinoid CB1receptor antagonists or inverse agonists such as rimonobant, ghrelinantagonists, oxyntomodulin, neuropeptide Y¹ or Y⁵ antagonists, 5-HT_(1B)receptor agonists, 5-HT_(2C) receptor agonists, 5-HT_(1B/2C) receptordual agonists, melanocortin receptor agonists, and melanin-concentratinghormone receptor antagonists, bupropion, naltrexone, topiramate, growthhormone analogues, and β3 agonists;(21) anti-dyslipidaemia agents, including: HMG-CoA reductase inhibitors,PPAR-α agonists, PPAR-α/γ dual agonists, bile acid sequestrants, ilealbile acid absorption inhibitors, acyl CoA:cholesterol acyltransferaseinhibitors, cholesterol absorption inhibitors, cholesterol estertransfer protein inhibitors, nicotinyl alcohol and its analogues, andanti-oxidants;(22) anti-inflammatory agents, including: non-steroidalanti-inflammatory drugs such as aspirin; and steroidal anti-inflammatoryagents such as hydrocortisone and dexamethasone;(23) anti-hypertensive agents, including: β-blockers such as atenololand inderal; calcium antagonists such as nifedipine; ACE inhibitors suchas lisinopril, aptopril and captopril; angiotensin receptor antagonistssuch as candesartan, losartan and cilexetil; diuretic agents such asfurosemide and benzthiazide; α-antagonists; centrally acting agents suchas clonidine, methyl dopa, and indapamide; renin inhibitors; andvasodilators such as hydralazine;(24) dipeptidyl peptidase IV (DPP-IV) inhibitors such as sitagliptin andsaxagliptin;(25) acetylcholinesterase inhibitors, including: donezepilhydrochloride, rivastigmine and galanthamine;(26) NMDA receptor blockers, including memantine hydrochloride;(27) Histamine H3 antagonists;(28) 5-HT₆ receptor antagonists;(29) α7 receptor agonists; and

(30) γ-secretase modulators, including tarenflurbil.

Other Uses

The PPPT compounds described herein may also be used as cell cultureadditives to inhibit 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1),etc.

The PPPT compounds described herein may also be used as part of an invitro assay, for example, in order to determine whether a candidate hostis likely to benefit from treatment with the compound in question.

The PPPT compounds described herein may also be used as a standard, forexample, in an assay, in order to identify other active compounds, other11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) a PPPTcompound as described herein, or a composition comprising a PPPTcompound as described herein, e.g., preferably provided in a suitablecontainer and/or with suitable packaging; and (b) instructions for use,e.g., written instructions on how to administer the compound orcomposition.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

Routes of Administration

The PPPT compound or pharmaceutical composition comprising the PPPTcompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, aplacental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g.,a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), alagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog),feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig),ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., amonkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g.,gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development,for example, a foetus.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the PPPT compound to be administered alone, itis preferable to present it as a pharmaceutical formulation (e.g.,composition, preparation, medicament) comprising at least one PPPTcompound, as described herein, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, including, but not limited to, pharmaceutically acceptablecarriers, diluents, excipients, adjuvants, fillers, buffers,preservatives, anti-oxidants, lubricants, stabilisers, solubilisers,surfactants (e.g., wetting agents), masking agents, colouring agents,flavouring agents, and sweetening agents. The formulation may furthercomprise other active agents, for example, other therapeutic orprophylactic agents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one PPPT compound, as describedherein, together with one or more other pharmaceutically acceptableingredients well known to those skilled in the art, e.g., carriers,diluents, excipients, etc. If formulated as discrete units (e.g.,tablets, etc.), each unit contains a predetermined amount (dosage) ofthe compound.

The term “pharmaceutically acceptable,” as used herein, pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbookof Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association thecompound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the compound with carriers (e.g.,liquid carriers, finely divided solid carrier, etc.), and then shapingthe product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, losenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or morecompounds and optionally one or more other pharmaceutically acceptableingredients, including, for example, penetration, permeation, andabsorption enhancers. Formulations may also suitably be provided in theform of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one ormore other pharmaceutically acceptable ingredients. The compound may bepresented in a liposome or other microparticulate which is designed totarget the compound, for example, to blood components or one or moreorgans.

Formulations suitable for oral administration (e.g., by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the compound in a flavoredbasis, usually sucrose and acacia or tragacanth. Pastilles typicallycomprise the compound in an inert matrix, such as gelatin and glycerin,or sucrose and acacia. Mouthwashes typically comprise the compound in asuitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine thecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g., povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g., lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc, silica);disintegrants (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g., sodium lauryl sulfate);preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid); flavours, flavour enhancing agents, and sweeteners.Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the compound therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or awater-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example, at least about 30% w/w of a polyhydric alcohol, i.e., analcohol having two or more hydroxyl groups such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycoland mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the compoundthrough the skin or other affected areas. Examples of such dermalpenetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase,which may optionally comprise merely an emulsifier (otherwise known asan emulgent), or it may comprise a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. Preferably, ahydrophilic emulsifier is included together with a lipophilic emulsifierwhich acts as a stabiliser. It is also preferred to include both an oiland a fat. Together, the emulsifier(s) with or without stabiliser(s)make up the so-called emulsifying wax, and the wax together with the oiland/or fat make up the so-called emulsifying ointment base which formsthe oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulfate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the compound is dissolved or suspended in a suitable carrier,especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the compound, such carriers as are known inthe art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additionally contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilisers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/mL to about 10 μg/mL,for example from about 10 ng/mL to about 1 μg/mL. The formulations maybe presented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the PPPT compounds, and compositions comprising the PPPTcompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular PPPT compound, the route ofadministration, the time of administration, the rate of excretion of thePPPT compound, the duration of the treatment, other drugs, compounds,and/or materials used in combination, the severity of the disorder, andthe species, sex, age, weight, condition, general health, and priormedical history of the patient. The amount of PPPT compound and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the PPPT compound is in the range ofabout 10 μg to about 250 mg (more typically about 100 μg to about 25 mg)per kilogram body weight of the subject per day. Where the compound is asalt, an ester, an amide, a prodrug, or the like, the amountadministered is calculated on the basis of the parent compound and sothe actual weight to be used is increased proportionately.

Examples Chemical Synthesis

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

Analytical Method 1:

The system consisted of a Hewlett Packard HP1100 LC system and a HigginsClipeus 5 μm C18 100×3.0 mm column maintained at 40° C. Detection wasachieved using a Waters Quattro Micro triple quadrupole massspectrometer (electrospray, positive ion and negative ion), a DAD UVdetector and a Sedex ELS 85 evaporative light scattering detector.Mobile Phase A: 0.1% aqueous formic acid. Mobile Phase B: 0.1% formicacid in MeOH. Flow rate 1 mL/min: Gradient: 0-1 min 15% B; 1-13 min15-95% B; 13-20 min 95% B; 20-22 min 95-15% B; 22-25 min 15% B.

Analytical Method 2:

The system consisted of a Waters Acquity HPLC system and an Acquity BEHC18 1.7 μm 100×2.1 mm column, maintained at 40° C. Detection wasachieved using a Waters Micromass ZQ2000 quadrupole mass spectrometer(electrospray, positive ion and negative ion), a PDA UV detector. MobilePhase A: 0.1% aqueous formic acid, Mobile

Phase B: 0.1% formic acid in MeCN. Flow rate 0.4 mL/min: Gradient: 0-0.4min 5% B; 0.4-6.0 min 5-95% B; 6-6.8 min 95% B; 6.8-7.0 min 95-5% B; 7-8min 5% B.

Analytical Method 3:

The system consisted of a Waters Acquity HPLC system and a HigginsClipeus 5 μm C18 100×3.0 mm column, maintained at 40° C. Detection wasachieved using a Waters Micromass ZQ2000 quadrupole mass spectrometer(electrospray, positive ion and negative ion), a PDA UV detector. MobilePhase A: 0.1% aqueous formic acid, Mobile Phase B: 0.1% formic acid inMeOH. Flow rate 1 mL/min: Gradient: 0-1 min 15% B; 1-13 min 15-95% B;13-20 min 95% B; 20-22 min 95-15% B; 22-25 min 15% B.

Analytical Method 4:

The system consisted of a Hewlett Packard 1050 LC system and a Luna 3 μmC18(2) 30×4.6 mm column. Detection was achieved using a Finnigan AQAsingle quadrupole mass spectrometer (electrospray, positive ion), a UVdiode array detector and a Sedex ELS 65 evaporative light scatteringdetector. Mobile Phase A: 0.1% aqueous formic acid, Mobile Phase B: 0.1%formic acid in MeOH. Flow rate 2 mL/min: Gradient: 0-0.5 min 5% B;0.5-4.5 min 5-95% B; 4.5-5 min 95% B; 5.5-6.0 min 95-5% B.

NMR Analysis

Proton NMR spectra were obtained using a Varian Unity Inova 400spectrometer operating at 400 MHz.

Abbreviations Bn=Benzyl.

DAST=Diethylaminosulphur trifluoride.

DCM=Dichloromethane. DIPEA=Diisopropylethylamine.DME=1,2-Dimethoxyethane. DMF=Dimethylformamide.

HATU=(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate).HCl=Hydrochloric acid.IMS=Industrial methylated spirit.Pearlman's catalyst=Palladium hydroxide on carbon.R.T.=Retention time.SM=Starting material.TFA=Trifluoroacetic acid.

THF=Tetrahydrofuran.

s=singlet.d=doublet.t=triplet.m=multiplet.q=quartet.

Compounds were named using Autonom.

Compounds containing chiral centres were prepared as racemic mixtures,unless stated otherwise.

Synthesis 1(4-Hydroxy-4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone(AA-01)

5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.04 g, 0.2 mmol) and4-phenyl-piperidin-4-ol (0.041 g, 0.23 mmol) were dissolved inacetonitrile (3 mL). HATU (0.24 mmol) and diisopropylethylamine (0.077mL, 0.45 mmol) were added and the reaction mixture was stirred. After 1hour the solvent was evaporated under vacuum and the residue stirredwith aqueous sodium hydroxide (1 N, 3 mL) for 0.5 hours. The mixture wasdiluted with ethyl acetate and washed with brine, dried over magnesiumsulphate, filtered and the solvent evaporated under vacuum. The residuewas purified by flash chromatography on silica eluting with ethylacetate. The fractions containing the desired product were concentratedunder vacuum to give the title compound (0.041 g) as a white solid.

LCMS m/z 354.2 [M+H]⁺ R.T.=8.94 min (Analytical Method 1). ¹H NMR (400MHz, d6-DMSO): δ 13.0 (s, 1H), 8.2 (s, 1H), 7.8 (s, 1H), 7.6 (s, 1H),7.5 (d, 2H), 7.3 (m, 3H), 7.2 (t, 1H), 5.2 (s, 1H), 4.4-3.2 (m broad,4H), 1.8-2.0 (m broad, 2H), 1.5-1.8 (m broad 2H).

The following compounds were prepared using methods analogous to thoseused to prepare(4-hydroxy-4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone.In some cases the product was purified by preparative HPLC on a C18cartridge, eluting with 40%-70% methanol/water with 0.1% formic acid;the fractions containing the desired product were concentrated undervacuum and further lyophilised from methanol and water to give the titlecompound.

MS Cmpd. Analytical R.T. [m/z] No. Structure Method (min) [M + H]⁺ AA-02

1 10.03 388.04 AA-03

1 10.27 422.05 AA-04

2  3.47 372.1  AA-05

1  9.14 372.1  AA-06

2  3.50 380.20 AA-07

2  3.93 406.01 AA-08

2  3.68 388.04 AA-09

2  3.62 390.07 AA-10

2  3.30 370.0  AA-11

2  4.15 422.0  AA-12

2  3.82 406.0  AA-13

2  3.69 368.11 AA-14

2  3.89 422.1  AA-15

1 10.62 368.1  AA-16

2  4.42 352.1  AA-17

3 10.66 356.1  AA-18

2  4.28 374.1  AA-19

2  9.17 368.1  AA-20

3  9.59 363.1  BB-01

3 10.62 356.1  BB-02

3  9.37 363.1  BB-03

1 10.96 368.4  BB-04

2  3.94 363.11 BB-05

1 10.75 356.25 BB-06

2  4.63 372.17 BB-07

2  4.32 356.15 BB-08

2  4.38 &  4.41 364.12 BB-09

2  4.36 404.8  BB-10

2  4.42 374.1  BB-11

1 11.09 352.2  AA-22

2  3.80 386.1  AA-23

2  3.69 406.0  AA-26

2  3.81 406.0  AA-37

2  4.58 407.9  AA-40

2  4.60 388.0  AA-36

2  4.45 390.0  AA-38

2  4.98 423.9  AA-35

2  4.63 390.0  AA-31

2  4.08 421.9  AA-28

2  3.46 390.0  AA-27

2  3.88 421.9  AA-24

2  4.10 421.9  AA-21

2  3.96 421.9  AA-29

2  3.77 402.0  BB-13

2  4.69 406.0  BB-12

2  4.45 352.1  BB-15

2  4.62 372.0  BB-14

2  3.38 368.1  AA-34

2  4.73 386.0  AA-33

2  4.36 401.9  AA-41

2  4.10 396.9  AA-25

2  3.54 410.1  AA-30

2  3.65 414.0  AA-32

2  3.67 380.1 

Additional ¹H NMR data for several of the above compounds is givenbelow:

Cmpd. No. ¹H NMR (400 MHz, d6-DMSO) δ: AA-04 13.1 (s, 1H), 8.1 (s broad,1H), 7.8 (m broad, 1H), 7.7 (t, 1H), 7.55 (s, 1H), 7.3 (m, 2H), 7.2 (t,1H), 7.1 (m, 1H), 5.4 (s, 1H), 4.4-3.8 (m, 2H), 3.7-3.1 (m broad, 2H),2.2-2.0 (m, broad, 2H), 1.8-1.6 (m broad, 2H). AA-06 13.1 (s, 1H), 8.15(s broad, 1H), 7.9 (s broad, 1H), 7.7 (s, 1H), 7.4 (m, 3H), 7.3 (t, 2H),7.2 (t, 1H), 5.1 (s, 1H), 4.6-4.4 (m broad, 2H), 2.4-1.8 (m broad, 8H).AA-07 13.1 (s, 1H), 8.1 (s broad, 1H), 7.8 (s broad, 1H), 7.7 (t, 1H),7.6 (s, 1H), 7.2-7.4 (m, 3H), 5.5 (s broad, 1H), 4.4-3.1 (m broad, 4H),2.2-2.0 (m, 2H) 1.7-1.5 (m broad, 2H). AA-08 13.1 (s, 1H), 8.1 (s, 1H),7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 2H), 7.3 (m, 2H), 5.4 (s, 1H), 4.4 (m,2H), 3.9-3.1 (m broad, 4H), 1.8-1.6 (m broad, 2H). AA-14 13.1 (s, 1H),8.1 (s, 1H), 7.8 (m, 3H), 7.6 (m, 2H), 7.5 (t, 1H), 7.2 (s, 1H), 5.25(s, 1H), 4.4-3.1 (m broad, 4H), 2.2-1.7 (m broad, 4H). AA-16 13.1 (s,1H), 8.1 (s, 1H), 7.8 (s, 1H), 7.5 (s, 1H), 7.4 (m, 2H), 7.3 (t, 2H),7.25 (s, 1H), 7.2 (t, 1H), 3.7-3.4 (m broad, 4H), 2.1 (m broad, 2H), 1.7(m broad, 2H), 1.1 (s, 3H). BB-04 13.1 (s, 1H), 8.1 (s broad, 1H), 7.8(m broad, 2H), 7.7 (t, 1H), 7.6 (m, 2H), 7.4 (t, 1H), 7.3 (s, 1H),4.6-4.1 (m broad, 2H), 3.4-2.8 (m broad, 3H), 1.9-1.6 (m broad, 4H).

The following piperidines used in the syntheses of analogues listedabove were commercially available:

4-(4-chloro-phenyl)- piperidin-4-ol

4-(3-trifluoromethyl-phenyl)- piperidin-4-ol

4-(4-fluoro-phenyl)- piperidine

4-piperidin-4-yl-benzonitrile

4-(2-methoxy-phenyl)- piperidine

4-(3-fluoro-phenyl)- piperidine

4-(2-fluoro-phenyl)- piperidine

4-(2-trifluoromethyl-phenyl)- piperidin-4-ol

4-phenyl-piperidine-4- carbonitrile

4-phenyl-piperidine

Other piperidines were prepared using the methods described below.

Synthesis 2 4-(2,4-Difluoro-phenyl)-4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester

1-Bromo-2,4-difluoro-benzene (0.67 g, 3.5 mmol) was dissolved in THF (5mL) and cooled to 0° C. Isopropylmagnesium chloride lithium chloridecomplex in THF (1.3 M, 2.5 mL, 3.2 mmol) was added. The mixture wasstirred for 0.5 hours then added dropwise to a solution of4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) inTHF (10 mL) that had been cooled to −78° C. The mixture was allowed towarm to room temperature then cooled to −78° C. and a solution ofsaturated aqueous ammonium chloride was added and the mixture extractedinto ethyl acetate, dried over magnesium sulphate, filtered and thesolvent removed by evaporation under vacuum. The residue was purified byflash chromatography on silica eluting with 0-50% ethyl acetate/hexane.The fractions containing the desired product were concentrated undervacuum to give the title compound (0.7 g) as a clear, colourless oil.LCMS m/z 314.3 [M+H]⁺. R.T.=4.65 min (Analytical Method 4).

Synthesis 3 4-(2,4-Difluoro-phenyl)-piperidin-4-ol

4-(2,4-Difluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester (0.2 g) was dissolved in a solution of hydrogenchloride in dioxane (4 N, 1 mL). The mixture was stirred for 1 hour andthe solvent removed by evaporation under vacuum. The solid wastriturated from ether to afford the title compound as a pale yellowsolid (0.08 g). LCMS m/z 214.25 [M+H]⁺. R.T.=1.06 min (Analytical Method4).

The following substituted piperidines were made by methods analogous tothose used to prepare 4-(2,4-difluoro-phenyl)-piperidin-4-ol from4-oxo-piperidine-1-carboxylic acid tert-butyl ester:

4-(2-fluoro-phenyl)-piperidin-4-ol

4-(4-fluoro-phenyl)-piperidin-4-ol

4-(4-chloro-2-fluoro-phenyl)- piperidin-4-ol

4-(2-chloro-phenyl)-piperidin-4-ol

4-(3,4-dichloro-phenyl)-piperidin-4-ol

4-(2-chloro-4-fluoro-phenyl)- piperidin-4-ol

4-(2-fluoro-6-methyl-phenyl)- piperidin-4-ol

4-(2-chloro-6-fluoro-phenyl)- piperidin-4-ol

4-(2-chloro-5-fluoro-phenyl)- piperidin-4-ol

4-(2,5-dichloro-phenyl)- piperidin-4-ol

4-(2,6-difluoro-phenyl)- piperidin-4-ol

4-(2,6-dichloro-phenyl)- piperidin-4-ol

4-(2,4-dichloro-phenyl)- piperidin-4-ol

4-(2,3-dichloro-phenyl)- piperidin-4-ol

Synthesis 4 8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol

A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was addeddropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixturewas stirred for 3 hours and a solution of saturated aqueous ammoniumchloride was added and the products extracted into diethyl ether, driedover sodium sulphate, filtered and the solvent removed by evaporationunder vacuum. The residue was purified by flash chromatography on silicaeluting with 10-30% ethyl acetate/hexane. The fractions containing thedesired product were concentrated under vacuum to give the titlecompound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]⁺. R.T.=2.59 min(Analytical Method 4).

The following compounds were made by methods analogous to those used toprepare 8-benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol:

8-benzyl-3-(2-methoxy- phenyl)-8-aza-bicyclo [3.2.1]octan-3-ol

8-benzyl-3-(2-chloro- phenyl)-8-aza-bicyclo [3.2.1]octan-3-ol

3-benzyl-8-phenyl-3-aza- bicyclo[3.2.1]octan-8-ol

Synthesis 5 3-Phenyl-8-aza-bicyclo[3.2.1]octan-3-ol

8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol (0.24 g, 0.84 mmol) wasdissolved in IMS (4.5 mL) and water (0.5 mL). Ammonium formate (0.5 g)and Pearlman's catalyst (0.12 g) were added. The mixture was heated toreflux for 0.5 hour, filtered and the solution concentrated to give anoil which was purified by chromatography on an SCX cartridge elutingwith ammonia (2 M) in methanol. The fractions containing the desiredproduct were concentrated under vacuum to give the title compound (0.13g) as an oil.

LCMS m/z 204.3 [M+H]⁺. R.T.=0.36 min (Analytical Method 4).

The following compounds were made by methods analogous to those used toprepare 3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol:

3-(2-methoxy-phenyl)-8-aza-bicyclo[3.2.1] octan-3-ol

8-phenyl-3-aza-bicyclo[3.2.1]octan-8-ol

Synthesis 6 4-Methoxy-4-phenyl-piperidine-1-carboxylic acid tert-butylester

4-Hydroxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 g,1.8 mmol) was dissolved in dry THF (15 mL) and sodium hydride (60% disp.in mineral oil; 0.076 g, 1.9 mmol) added and the mixture stirred for 1hour. Methyl iodide (0.16 mL; 2.7 mmol) was then added and the mixturestirred overnight. Brine was added and the product extracted into ethylacetate, dried over sodium sulphate, filtered and the solvent removed byevaporation. The residue was purified by flash chromatography on silicaeluting with 0-10% ethyl acetate/hexane. The fractions containing thedesired product were concentrated under vacuum to give the titlecompound as a clear colourless oil (0.35 g).

LCMS m/z 292.4 [WH]⁺. R.T.=4.86 min (Analytical Method 4).

Synthesis 7 4-Methoxy-4-phenyl-piperidine

4-Methoxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.35g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 3mL). The mixture was stirred for 1 hour and the solvent removed byevaporation under vacuum. The solid was triturated from ether to affordthe title compound as a white solid (0.25 g). LCMS m/z 192.2[M+H]⁺.R.T.=1.96 min (Analytical Method 4).

The following substituted piperidine was made by methods analogous tothose used to prepare 4-methoxy-4-phenyl-piperidine:

4-(2-chloro-phenyl)-4-methoxy-piperidine

Synthesis 8 1-Benzyl-4-methyl-piperidin-4-ol

1-Benzyl-4-piperidine (1.0 g, 5.2 mmol) was dissolved in dry diethylether (10 mL) and cooled to −78° C. Methyl lithium in diethyl ether (1.6M; 4.6 mL, 7.4 mmol) was added and the mixture stirred for 1.5 hours.The mixture was diluted with water and the products extracted intodiethyl ether, dried over magnesium sulphate, filtered and the solventremoved by evaporation under vacuum. The residue was purified by flashchromatography on silica eluting with 0-10% ethyl acetate/methanol. Thefractions containing the desired product were concentrated under vacuumto give the title compound as a yellow oil (0.35 g). LCMS m/z206.27[M+H]⁺. R.T.=0.83 min (Analytical Method 4).

Synthesis 9 1-Benzyl-4-(4-bromo-phenyl)-4-methyl-piperidine

To a solution of 1-benzyl-4-methyl-piperidin-4-ol (0.4 g, 1.95 mmol) inbromobenzene (1.2 mL) was added aluminium trichloride (0.39 g, 2.9mmol). The mixture was then heated to 100° C. for 14 hours and leftstanding at room temperature for 48 hours. Aqueous sodium hydroxide (1N, 30 mL) was added and the products extracted into ethyl acetate, driedover magnesium sulphate, filtered and the solvent removed by evaporationunder vacuum. The residue was purified by flash chromatography on silicaeluting with 0-25% ethyl acetate/hexane. The fractions containing thedesired product were concentrated under vacuum to give the titlecompound as a brown oil (0.5 g). LCMS m/z 344.5 [M+H]⁺. R.T.=3.13 min(Analytical Method 4).

Synthesis 10 4-Methyl-4-phenyl-piperidine hydrochloride

1-Benzyl-4-(4-bromo-phenyl)-4-methyl-piperidine (0.35 g, 1.0 mmol) wasdissolved in IMS (20 mL) and palladium on carbon (10%; 0.15 g) in water(2 mL) was added under nitrogen. Ammonium formate (0.63 g, 10 mmol) wasadded and the mixture heated at reflux for 0.5 hour. The mixture wasallowed to cool, filtered and the solvent removed by evaporation undervacuum. The residue was treated with a solution of hydrogen chloride indioxane (4 M; 0.5 mL) followed by trituration from diethylether to givethe title compound as a white solid (0.095 g). LCMS m/z 176.2 [M+H]⁺.R.T.=2.21 min (Analytical Method 4).

Synthesis 11 1-Benzyl-4-phenyl-piperidin-4-ol

4-Hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol), benzylbromide (0.5 g, 3mmol) and potassium carbonate (0.8 g, 6 mmol) were dissolved in DMF (5mL) and stirred for 2 hours. The mixture was diluted with ethyl acetateand washed with a solution of saturated aqueous sodium carbonatesolution then dried over magnesium sulphate, filtered and the solventremoved by evaporation under vacuum. The resulting solid wasrecrystallised from pentane to give the title compound as a white solid(0.47 g). LCMS m/z 268.3 [M+H]⁺. R.T.=2.37 min (Analytical Method 4).

Synthesis 12 1-Benzyl-4-fluoro-4-phenyl-piperidine

1-Benzyl-4-phenyl-piperidin-4-ol (0.45 g, 1.69 mmol) in DCM (20 mL) wascooled to −78° C. Diethylaminosulphur trifluoride (2 mmol) was added andthe mixture stirred for 0.5 hour and allowed to warm to roomtemperature. The mixture was diluted with DCM and washed with water,dried over magnesium sulphate, filtered and the solvent removed byevaporation under vacuum. The oil was used without further purification.LCMS m/z 270.3 [M+H]⁺. R.T.=2.87 min (Analytical Method 4).

Synthesis 13 1-Benzyl-4-phenyl-piperidin-4-ol

To 1-benzyl-4-fluoro-4-phenyl-piperidine (0.22 g) in dry DCM (5 mL) wasadded 1-chloroethylchloroformate (1 mmol). The mixture was stirred for 1hour and then methanol (5 mL) was added and the mixture stirredovernight. The solvent was removed under vacuum, and the resulting solidtriturated from diethyl ether to give the title compound as a whitesolid (0.12 g). LCMS m/z 180.1 [M+H]⁺. R.T.=2.27 min (Analytical Method4).

Synthesis 14 4-Fluoro-4-(2-fluoro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

4-(2-Fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butylester (0.5 g, 1.69 mmol) in DCM (20 mL) was cooled to −78° C.Diethylaminosulphur trifluoride (2 mmol) was added and the mixturestirred for 0.5 hour and allowed to warm to room temperature. Themixture was diluted with DCM and washed with water then dried overmagnesium sulphate, filtered and the solvent removed by evaporationunder vacuum to give the title compound as a brown oil which was usedwithout further purification. LCMS m/z 298.3 [M+H]⁺. R.T.=4.97 min(Analytical Method 4).

Synthesis 15 4-Fluoro-4-(2-fluoro-phenyl)-piperidine hydrochloride

4-Fluoro-4-(2-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butylester (0.4 g, 1.35 mmol) was dissolved in a solution of hydrogenchloride in dioxane (4 M, 3 mL) and the mixture stirred for 1 hour. Thesolvent was evaporated under vacuum, and the resulting solid trituratedfrom diethyl ether to give the title compound as a pale yellow solid(0.26 g) which was used without further purification.

The following substituted piperidines were made by methods analogous tothose used to prepare 4-fluoro-4-(2-fluoro-phenyl)-piperidinehydrochloride from 4-fluoro-4-(2-fluoro-phenyl)-piperidine-1-carboxylicacid tert-butyl ester:

4-(2-chloro-5-fluoro-phenyl)-4-fluoro- piperidine

4-fluoro-4-(2-fluoro-6-methyl-phenyl)- piperidine

4-(2-chloro-phenyl)-4-fluoro- piperidine

4-(2,4-dichloro-phenyl)-4-fluoro- piperidine

4-(4-chloro-phenyl)-4-fluoro- piperidine

Synthesis 16 4-(2-Cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (0.5 g, 1.5 mmol), 2-cyanophenylboronic acid (0.23 g,1.6 mmol), tetrakis-triphenylphosphine (0.17 g, 0.15 mmol) and cesiumcarbonate (0.73 g, 2.26 mmol) were dissolved in a mixture of DME (3 mL),IMS (1.0 mL) and water (0.4 mL) under argon. The mixture was heated bymicrowave irradiation to 120° C. for 0.3 hours then diluted with water.The products were extracted into DCM, dried over magnesium sulphate,filtered and the solvent removed by evaporation under vacuum. Theresidue was purified by flash chromatography on silica eluting with0-20% ethyl acetate/hexane. The fractions containing the desired productwere concentrated under vacuum to give the title compound as a yellowoil (0.22 g). LCMS m/z 261.2 [M+H]⁺. R.T.=4.59 min (Analytical Method4).

The following substituted piperidines were made by methods analogous tothose used to prepare4-(2-cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester from4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester:

4-(2-nitro-phenyl)-3,6- dihydro-2H-pyridine-1- carboxylic acidtert-butyl ester

4-(2-methoxycarbonyl- phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acidtert-butyl ester

Synthesis 17 4-(2-Cyano-phenyl)-piperidine-1-carboxylic acid tert-butylester

4-(2-Cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (0.2 g) was dissolved in IMS (15 mL) and palladium on carbon (10%;0.08 g) in water (0.5 mL) was added. Ammonium formate (0.3 g) was addedand the mixture heated at reflux for 0.5 hour. The mixture was allowedto cool, filtered and the solvent removed by evaporation to give thetitle compound as a clear colourless oil (0.15 g). LCMS m/z 287.3[M+H]⁺.R.T.=4.63 min (Analytical Method 4).

The following substituted piperidine was made by methods analogous tothose used to prepare 4-(2-cyano-phenyl)-piperidine-1-carboxylic acidtert-butyl ester from4-(2-cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester:

4-(2-methoxycarbonyl- phenyl)-piperidine-1- carboxylic acid tert- butylester

Synthesis 18 2-Piperidin-4-yl-benzonitrile

4-(2-Cyano-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15g) was dissolved in a solution of hydrogen chloride in dioxane (4 M, 2mL) and the mixture stirred for 1 hour. The solvent was evaporated undervacuum, and the resulting solid triturated from diethyl ether to givethe title compound as a grey solid (0.1 g). LCMS m/z 187.2[M+H]⁺.R.T.=1.90 min (Analytical Method 4).

The following substituted piperidines were made by analogous methods tothose used to prepare 2-piperidin-4-yl-benzonitrile from4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester:

4-(4-chloro-phenyl)-piperidine

4-(2-difluoromethoxy-phenyl)- piperidine

4-(2-trifluoromethyl-phenyl)- piperidine

4-o-tolyl-piperidine

Synthesis 19 8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]oct-2-ene

8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol (0.1 g, 0.34 mmol) wasdissolved in TFA (1 mL) and cooled to 0° C. Concentrated sulphuric acid(0.054 mL) was added and the mixture stirred for 1 hour, thentriethylsilane (0.17 mL) was added. After 2 hours the mixture wasallowed to warm to room temperature, and then to stand for 60 hours. Themixture was concentrated under vacuum and diluted with a solution ofsaturated aqueous sodium carbonate. The products were extracted intoDCM, dried over magnesium sulphate, filtered and the solvent removed byevaporation under vacuum to give the title compound as a colourless oil.LCMS m/z 276.5 [M+H]⁺. R.T.=2.94 min (Analytical Method 4).

Synthesis 20 3-Phenyl-8-aza-bicyclo[3.2.1]octane

8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]oct-2-ene (0.1 g) was dissolved inIMS (5 mL) and water (0.5 mL). Ammonium formate (0.21 g) and Pearlman'scatalyst (0.02 g) were added and the mixture heated to 90° C. for 1hour. After cooling, the mixture was filtered and concentrated undervacuum. The residue was purified on an SCX cartridge, eluting withaqueous ammonia (2 M) and methanol. The fractions containing the desiredproduct were concentrated under vacuum to give the title compound as acolourless oil. LCMS m/z 188.4 [M+H]⁺. R.T.=2.22 min (Analytical Method4).

Synthesis 21 4-(2,4-Difluoro-phenyl)-1,2,3,6-tetrahydro-pyridine

4-(2,4-Difluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester (0.4 g) was dissolved in toluene (10 mL). Concentratedsulphuric acid (0.3 mL) was added and the mixture was heated at refluxfor 2 hours and then allowed to stand at room temperature overnight. Asolution of aqueous sodium hydroxide (1 N, 30 mL) was added and theproducts extracted into ethyl acetate. The organic solution was driedwith magnesium sulphate, filtered and the solvent removed by evaporationunder vacuum to give the title compound as a dark oil (0.2 g) which wasused without further purification. LCMS m/z 196.1 [M+H]⁺. R.T.=2.12 min(Analytical Method 4).

Synthesis 22 4-(2,4-Difluoro-phenyl)-piperidine hydrochloride

4-(2,4-Difluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (0.2 g) wasdissolved in ethanol (15 mL). Palladium on carbon (10%; 0.02 g) wasadded under nitrogen. The nitrogen atmosphere was replaced by hydrogenand the mixture stirred for 36 hours. The mixture was filtered and thesolvent removed by evaporation under vacuum. The residue was dissolvedin ethyl acetate and a solution of hydrogen chloride in dioxane (4 N, 1mL) added. The resulting precipitate was isolated by filtration, washedwith ether and dried under vacuum to give the title compound as a whitesolid (0.15 g). LCMS m/z 198.1[M+H]⁺. R.T.=2.21 min (Analytical Method4).

Synthesis 23 1-Benzyl-4-(2-benzyloxy-phenyl)-piperidin-4-ol

A solution of 1-benzyl-4-piperidone (0.5 g, 2.6 mmol) in THF (10 mL) wascooled to −78° C. and 2-(benzyloxy)phenyl magnesium bromide (3.2 mmol)was added. The mixture was stirred for 0.5 hours then allowed to warm toroom temperature. Hydrochloric acid (1 N, 10 mL) was added carefully andthe mixture stirred for 0.1 hour before adding a solution of aqueoussodium hydroxide (1 N, 30 mL). The products were extracted into ethylacetate, dried over magnesium sulphate, filtered and the solvent removedby evaporation under vacuum. The residue was purified by flashchromatography on silica eluting with 0-50% ethyl acetate/hexane. Thefractions containing the desired product were concentrated under vacuumto give the title compound (0.6 g) as a clear, colourless oil.

LCMS m/z 374.5 [M+H]⁺. R.T.=3.44 min (Analytical Method 4).

Synthesis 24 4-(2-Hydroxy-phenyl)-piperidin-4-ol hydrochloride

1-Benzyl-4-(2-benzyloxy-phenyl)-piperidin-4-ol (0.6 g, 1.6 mmol) wasdissolved in ethanol (30 mL) and a suspension of palladium on carbon(10%; 0.3 g) in water (5 mL) was added. Ammonium formate (1 g) was addedand the mixture heated at reflux for 0.5 hour. The mixture was allowedto cool, filtered and the solvent removed by evaporation under vacuum.The residue was dissolved in diethyl ether and a solution of hydrogenchloride in dioxan (4 N, 1 mL) added. The resulting precipitate wasisolated by filtration, washed with diethyl ether and dried under vacuumto give the title compound as a white solid (0.2 g). LCMS m/z 194.3[M+H]⁺. R.T.=0.35 min (Analytical Method 4).

Synthesis 25 (4-Phenyl-piperidin-4-yl)-methanol

4-Phenyl-piperidine-4-carboxylic acid (1.0 g, 2.7 mmol) was added to asolution of borane in THF (1 M, 15 mL). The mixture was then heated atreflux for 1 hour, and then methanol (3 mL) was carefully addeddropwise. The mixture was heated at reflux for 1 hour and allowed tocool to room temperature and hydrochloric acid (1 N, 2 mL) was added andthe mixture left to stand overnight. The solvent was then removed byevaporation under vacuum and the residue triturated with acetone. Theresulting solid was isolated by filtration, washed with diethyl etherand dried under vacuum to afford the title compound as a white solid(0.37 g). LCMS m/z 192.2 [M+H]⁺. R.T.=0.69 min (Analytical Method 4).

Synthesis 26 5-Bromo-thiophene-3-carboxylic acid

Thiophene-3-carboxylic acid (25 g, 195 mmol) was dissolved in aceticacid (200 mL). Bromine (10.4 mL, 200 mmol) was added slowly over thecourse of 0.5 hour. The mixture was stirred for a further 0.5 hour andthen poured onto ice. After 0.5 hours the white precipitate that formedwas collected by filtration. Recrystallisation from water gave the titlecompound as a white solid (13.7 g). ¹H NMR (400 MHz, d₆-DMSO): δ 8.25(s, 1H), 7.45 (s, 1H).

Synthesis 27 5-Bromo-thiophene-3-carboxylic acid methyl ester

5-Bromo-thiophene-3-carboxylic acid (13 g, 64 mmol) was dissolved inmethanol (140 mL). Concentrated sulphuric acid (6.5 mL) was added andthe mixture heated at reflux for 14 hours. The reaction was quenched byadding a solution of saturated aqueous sodium bicarbonate and most ofthe solvent was removed by evaporation under vacuum. The mixture wasthen diluted with a solution of saturated aqueous sodium bicarbonate andthe product extracted with DCM. The organic solution was dried oversodium sulphate, filtered and the solvent removed by evaporation to givea white crystalline solid (13.2 g). ¹H NMR (400 MHz, CDCl₃): δ 8.0 (s,1H), 7.5 (s, 1H), 3.85 (s, 3H).

Synthesis 28 5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid methylester

5-Bromo-thiophene-3-carboxylic acid methyl ester (6 g, 27 mmol) wasdissolved in a mixture of DME (75 mL), IMS (25 mL) and water (12.5 mL).Caesium carbonate (13.2 g, 40 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (9.2 g, 31 mmol) were added and the mixturestirred under argon. Palladium tetrakis-(triphenylphosphine) (3.1 g, 2.7mmol) was then added and the mixture heated at 110° C. for 6 hours. Themixture was allowed to cool to room temperature and then diluted withwater. The product was extracted into DCM and washed with brine, thendried over sodium sulphate, filtered and the solvent removed byevaporation under vacuum. The residue was triturated with diethyl etherto give the title compound as a pale yellow solid (3.01 g). LCMS m/z209.1 [M+H]⁺. R.T.=3.72 min (Analytical Method 4). ¹H NMR (400 MHz,d6-DMSO): δ 8.2 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.5 (s, 1H), 3.8(s, 3H).

Synthesis 29 5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid

5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid methyl ester (2.8 g,13.3 mmol) was dissolved in a mixture of methanol (18 mL) and a solutionof aqueous sodium hydroxide (1 N, 18 mL) and the mixture stirred at 50°C. for 1.5 hours. The mixture was concentrated under vacuum andacidified with aqueous hydrochloric acid (1N). The resulting precipitatewas isolated by filtration and washed with water before drying undervacuum to give the title compound as a white solid (1.77 g). LCMS m/z195.1 [M+H]⁺. R.T.=3.23 min (Analytical Method 4). ¹H NMR (400 MHz,d6-DMSO): δ 8.1 (s, 1H), 8.0 (m, 2H), 7.45 (s, 1H).

The following substituted carboxylic acid was made by analogous methodsto those used to prepare 5-(1H-pyrazol-4-yl)-thiophene-3-carboxylic acidfrom 5-bromo-thiophene-3-carboxylic acid methyl ester:

5-(3-methyl-1H-pyrazol-4-yl)- thiophene-3-carboxylic acid

Synthesis 30 4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridinehydrochloride

4-(2-Nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (0.45 g) was dissolved in a solution of hydrogen chloride indioxane (4 N, 4 mL). After stirring for 0.5 hour at 50° C., the solventwas removed by evaporation and the residue triturated with diethyl etherto give the title compound as a white solid (0.29 g). LCMS m/z 205.2[M+H]⁺. R.T.=3.80 min (Analytical Method 4).

Synthesis 31 1-[4-(2-Nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone

4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (0.44 g,1.8 mmol) was dissolved in a solution of pyridine (0.4 mL) and DCM (20mL). Acetyl chloride (0.142 mL) was added and the mixture was stirredfor 0.5 hours. The mixture was diluted with DCM (20 mL) and the organicsolution washed with water then 1 N hydrochloric acid. The solution wasdried with magnesium sulphate, filtered and the solvent removed byevaporation under vacuum to give the title compound as an orange oil(0.4 g). LCMS m/z 247.4 [M+H]⁺. R.T.=3.70 min (Analytical Method 4).

Synthesis 32 1-[4-(2-Amino-phenyl)-piperidin-1-yl]ethanone

1-[4-(2-Nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone (0.43 g, 1.8mmol) was dissolved in a solution of ammonium formate (1.13 g, 18 mmol)in IMS (20 mL) and water (20 mL). Palladium on carbon (10% w/w, 0.2 g)was then added and the mixture heated at reflux for 1 hour. The solutionwas filtered and then the solvent removed by evaporation under vacuum.The residue was dissolved in ethyl acetate (50 mL) and the resultingsolution washed with saturated aqueous sodium hydrogen carbonatesolution, dried over magnesium sulphate, filtered and the solventremoved by evaporation under vacuum to give the title compound as a palepink oil (0.3 g). LCMS m/z 219.38 [M+H]⁺. R.T.=2.29 min (AnalyticalMethod 4).

Synthesis 33 1-[4-(2-Chloro-phenyl)-piperidin-1-yl]-ethanone

1-[4-(2-Amino-phenyl)-piperidin-1-yl]-ethanone (0.3 g, 1.38 mmol) wasdissolved in a solution of hydrochloric acid (6 N, 6 mL) and cooled to0° C. A solution of sodium nitrite (0.097 g, 1.4 mmol) in water (1 mL)was added drop wise and the mixture stirred for 1 hour. The resultingsolution was added drop wise to a solution of copper (I) chloride (0.35g, 3.5 mmol) in hydrochloric acid (6 N, 6 mL). The mixture was allowedto warm to room temperature, and was then diluted with water (20 mL) andthe products extracted into ethyl acetate. The organic solution waswashed with water (20 mL) then dried over magnesium sulphate, filteredand the solvent removed by evaporation under vacuum to give the titlecompound as an orange oil (0.2 g). LCMS m/z 238.2 [M+H]⁺. R.T.=4.30 min(Analytical Method 4).

Synthesis 34 4-(2-Chloro-phenyl)-piperidine hydrochloride

1-[4-(2-Chloro-phenyl)-piperidin-1-yl]-ethanone (0.2 g) was dissolved ina solution of aqueous sodium hydroxide (1 N, 5 mL) and ethanol (10 mL)and heated to 50° C. for 6 hours. The solvent was removed by evaporationunder vacuum, and the products extracted into ethyl acetate, washed withwater (20 mL) then dried over magnesium sulphate, filtered and thesolvent removed by evaporation under vacuum. The residue was dissolvedin a solution of hydrogen chloride in dioxane (4 N, 1 mL) and thesolvent evaported to give the title compound as a pale yellow solid(0.12 g). LCMS m/z 196.1 [M+H]⁺. R.T.=2.46 min (Analytical Method 4).

Synthesis 35 4-(2-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

Lithium aluminium hydride (0.026 g, 0.7 mmol) was suspended in dry THF(1 mL) under a nitrogen atmosphere and cooled in an ice bath. A solutionof 4-(2-methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butylester (0.27 g, 0.7 mmol) in dry THF (2 mL) was added drop wise and thereaction mixture stirred for 1 hour. The reaction mixture was dilutedwith diethyl ether (5 mL) and quenched with hydrochloric acid (1 N, 5mL). The organic solution was separated and washed with saturatedaqueous sodium hydrogen carbonate (5 mL) and brine (5 mL), dried overmagnesium sulphate, filtered and the solvent removed under vacuum togive the title compound as a colourless gum (0.13 g). LCMS m/z 292.0[M+H]⁺. R.T.=4.57 min (Analytical Method 4).

Synthesis 36 (2-Piperidin-4-yl-phenyl)-methanol hydrochloride

4-(4-(2-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butylester (0.13 g, 0.44 mmol) was dissolved in a solution of hydrogenchloride in dioxane (4 N, 2 mL). The mixture was stirred for 1 hour andthe solvent removed by evaporation under vacuum. The solid wastriturated from ether to afford the title compound as a white solid(0.08 g). LCMS m/z 192.2 [M+H]⁺. R.T.=0.72 min (Analytical Method 4).

Synthesis 37 1-Benzyl-4-methyl-piperidin-4-ol

A solution of 1-benzyl-4-piperidone (26.5 mmol, 5 g) in THF (50 mL) wascooled to −15° C. and a solution of methyl magnesium bromide in ether (3M, 22 mL) was added. The mixture was stirred for 0.5 hours then allowedto warm to room temperature. Saturated aqueous ammonium chloride (50 mL)was added and the products were extracted into ethyl acetate, dried overmagnesium sulphate, filtered and the solvent removed by evaporationunder vacuum to give the title compound as a pale yellow solid (5.0 g)that was used directly without further purification.

Synthesis 38 1-Benzyl-4-(2-chloro-phenyl)-4-methylpiperidine

1-Benzyl-4-methyl-piperidin-4-ol (4.5 g) was dissolved in chlorobenzene(50 mL). Aluminium trichloride (15 g) was added portion wise and themixture then heated at reflux for 0.5 hours. The mixture was thenallowed to cool and poured over ice. The resulting solution was treatedwith sodium hydroxide until basic and the products extracted into ethylacetate, dried over magnesium sulphate, filtered and the solvent removedby evaporation under vacuum. The residue was purified by silicachromatography eluting with a mixture of ethyl acetate and hexane. Thefractions containing the desired products were combined and the solventremoved by evaporation to give a 4:1 mixture of the title compound and1-benzyl-4-(4-chloro-phenyl)-4-methyl-piperidine which was used directlywithout further purification.

Synthesis 39 4-(2-Chloro-phenyl)-4-methyl-piperidine

The mixture of 1-benzyl-4-(2-chloro-phenyl)-4-methylpiperidine and1-benzyl-4-(4-chloro-phenyl)-4-methyl-piperidine (1.6 g) was dissolvedin methanol (30 mL) and 1-chloroethylchloroformate (0.9 mL) was added.The mixture was heated at reflux for 10 minutes and allowed to cool. Thesolvent was removed by evaporation under vacuum and the residueprecipitated from ethyl acetate with ether to give a 4:1 mixture of thetitle compound and 4-(4-chloro-phenyl)-4-methyl-piperidine which wasused directly without further purification. LCMS m/z 210.2 [M+H]⁺.R.T.=2.64 min (Analytical Method 4).

Synthesis 40 4-(2-Chloro-phenyl)-4-cyano-piperidine-1-carboxylic acidtert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 1.28 g, 45 mmol) wassuspended in DMF (20 mL) and cooled in an ice bath under a nitrogenatmosphere. (2-Chloro-phenyl)-acetonitrile (1.77 g, 11.7 mmol) in DMF (5mL) was added slowly, and the mixture stirred for 2 hours.Bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol)in DMF (5 mL) was then added and the mixture heated to 75° C. for 6hours. The solvent was removed by evaporation under vacuum and theresidue dissolved in ethyl acetate (50 mL), washed with water, thenbrine, dried over magnesium sulphate, filtered and the solvent removedby evaporation under vacuum. The residue was purified by silicachromatography eluting with a mixture of ethyl acetate and hexane. Thefractions containing the desired products were combined and the solventremoved by evaporation to give the title compound as an orange gum (1.1g). LCMS m/z 321.0 [M+H]⁺. R.T.=4.76 min (Analytical Method 4).

Synthesis 41 4-(2-Chloro-phenyl)-piperidine-4-carbonitrile hydrochloride

4-(2-Chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butylester (0.25 g, 0.78 mmol) was dissolved in a solution of hydrogenchloride in dioxane (4 N, 1 mL). The mixture was stirred for 1 hour andthe solvent removed by evaporation under vacuum. The solid wastriturated from ether to afford the title compound as a yellow solid(0.178 g). LCMS m/z 221.2 [M+H]⁺. R.T.=2.18 min (Analytical Method 4).

Synthesis 42 3-(2-Chloro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol

8-Benzyl-3-(2-chloro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol (0.30 g,0.93 mmol) was dissolved in methanol (5 mL) and1-chloroethylchloroformate (0.14 mL) was added. The mixture was heatedat reflux for 6 hours and allowed to cool. The solvent was removed byevaporation under vacuum and the residue precipitated from ethyl acetatewith ether to give a white solid (0.12 g, 56%). LCMS m/z 287.2 [M+H]⁺.R.T.=1.96 min (Analytical Method 4).

Synthesis 43(8-Fluoro-8-phenyl-3-aza-bicyclo[3.2.1]oct-3-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]methanone(AA-39)

(8-Hydroxy-8-phenyl-3-aza-bicyclo[3.2.1]oct-3-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]methanone(0.05 g, 0.12 mmol) in DCM (2 mL) was cooled to −78° C. under anatmosphere of nitrogen. Diethylaminosulphur trifluoride (0.05 mL) wasadded and the mixture stirred for 0.25 hour and allowed to warm to roomtemperature over 1 hour. The mixture was diluted with DCM and washedwith water then dried over magnesium sulphate, filtered and the solventremoved by evaporation. The residue was purified by reverse phase HPLCand the fractions containing the desired products were combined and thesolvent removed by lyophilisation to give the title compound as a whitesolid (0.02 g). LCMS m/z 382.1 [M+H]⁺. RT.=4.25 min (Analytical Method2).

Biological Methods

Cellular In Vitro 11β-HSD1 Enzyme Inhibition Assay

Compounds were assessed by a Scintillation Proximity Assay (SPA)performed according to the following protocol:

HEK293 cells were stably transfected with a construct containing thefull-length gene coding for the human 11β-HSD1 enzyme to createHEK293/11β-HSD1 cells. Cells were routinely cultured in DMEM containing10% calf foetal serum, 1% glutamine, and 1% penicillin and streptomycin.Prior to assay, cells were plated at 2×10⁴ cells/well in 96-wellpoly-D-Lys coated flat-bottomed microplates and incubated in 5% CO₂, 95%O₂ at 37° C. for 24 hours. The media in each well was removedimmediately before assay.

Compounds to be tested were dissolved in DMSO at 10 mM and seriallydiluted into water containing 10% DMSO. Diluted compounds at a volume of10 μL were added to wells of a 96-well V-bottomed microplate. A solutionof DMEM, 1% glutamine, 1% penicillin and streptomycin, and 22 nMtritiated cortisone was prepared and 90 μL added to each well of theassay plate. This solution (100 μL/well) was transferred to the platecontaining the cells. The plate was then incubated in 5% CO₂, 95% O₂ at37° C. for 2 hours.

Following this incubation, 50 μL of the assay solution was transferredto each well of a 96-well scintillation microplate. A mixture consistingof anti-mouse YSi SPA beads, pre-mixed with anti-cortisol antibody inassay buffer (50 mM Tris.HCl, pH 7.0; 300 mM NaCl; 1 mM EDTA, 5%glycerol) was prepared and 50 μL added to each well of the scintillationmicroplate. An adhesive strip was applied to the microplate and theplate gently shaken for at least 2 hours at room temperature, and thenspun briefly on a low speed centrifuge. The plate was read on ascintillation counter suitable for 96-well microplates. For thecalculation of percentage inhibition, a series of wells were added tothe plate that represented the assay maximum and the assay minimum: oneset that contained substrate without cells (minimum) and another setthat contained substrate and cells without any compound (maximum).

The calculation of median inhibitory concentration (IC₅₀) values for thecompounds was performed using GraphPad Prism® software. Dose-responsecurves for each compound were plotted as fractional inhibition and datafitted to the four parameter logistic equation.

Cellular In Vitro 11β-HSD2 Enzyme Inhibition Assay

For measurement of inhibition of 11β-HSD2, CHO cells stably transfectedwith the full-length gene coding for human 11β-HSD2 were used. Assayswere carried out in 96-well microplates containing 1×10⁵ cells/well.Controls and compounds were plated as above, so that the final DMSOconcentration in each well was 1%. To initiate the assay, 90 μL of asolution of HAMS F-12 medium containing 1% glutamine, 1% penicillin andstreptomycin, and 22 nM tritiated cortisol was added to each well of theassay plate. The plate was then incubated in 5% CO₂, 95% O₂ at 37° C.for 16 hours.

The assay solutions were transferred to glass tubes and 20 μL ethylacetate added to each tube. Each tube was vortexed thoroughly and theupper layer containing the tritiated steroid transferred to a freshglass tube. The solvent was evaporated by placing the tubes in a heatingblock at 65° C. under a stream of Nitrogen gas. 20 μL ethanol was addedto each of the dried samples and vortexed briefly. Each sample wasapplied to a silica TLC plate and the plate dried. The plate was placedvertically in a glass tank containing 92% chloroform:8% ethanol and thesolvent allowed to rise up the plate. The plate was dried, placed in animaging cassette, and overlayed with a tritium imaging plate for 1-2days. The amount of enzyme inhibition in each sample was determined bymeasuring the intensity of the substrate and product spots using aphosphoimager.

IC₅₀ values for inhibitors were determined as described for 11β-HSD1.

In Vitro Human Liver Microsomal Stability Assay

To predict in vivo metabolism of compounds, the stability of compoundsincubated with human liver microsomes in vitro was determined. Humanliver microsome preparations were stored at −80° C. and thawed on iceprior to use. The thawed microsomes were diluted to a concentration of 2mg/mL in 50 mM sodium phosphate, pH 7.4. Reference and test compoundswere prepared as 10 mM stocks in 100% DMSO and diluted to 1 mM inacetonitrile before use. Each compound was tested in triplicate asfollows:

4 μL of test or reference compound was added to a well of a 24-wellmicroplate and 0.5 mL of 4 mM NADPH added. The plate was thentransferred to a shaker for 10 minutes at room temperature. 30 μL of thecompound/NADPH solution was transferred to the well of a 96-wellmicroplate and incubated at 37° C. for 5 minutes. 30 μL of human livermicrosomes (pre-incubated at 37° C. for 5 minutes) was added to the wellcontaining the compound/NADPH solution and the plate incubated for theselected period of time (typically 0 or 30 minutes). The reaction wasstopped by adding 60 μL of ice cold 300 μM trichloroacetic acid. Theplate was centrifuged at 1000 rpm for 5 minutes at room temperature andthe supernatant transferred to the well of a new 96-well v-bottomedmicroplate for mass spectrometric analysis.

Samples were analyzed by TSQ Quantum Discovery Tandem Mass Spectrometerand Surveyor Liquid Chromatogram (Thermo, Hemel-Hempstead, UK). 10 μL ofeach sample was injected in a mobile phase consisting of 60%:40%methanol:5 mM ammonium acetate at a flow rate of 0.5 mL/minute. Thecolumn used was a BDS hypersil, C18, 50×2.1 mm with a 5 μm particlesize.

Each compound was tuned with a spray voltage of 3000 V and a capillarytemperature of 300° C. and values for tube lens, CID and product ionswere determined.

The peak area for each compound was measured in triplicate for the 0 and30 minute samples and the average of each was reported. The percentageremaining after 30 minutes was calculated as the average peak area ofthe sample after 30 minutes divided by the average peak area at 0minutes. The RSD was 10% or lower for each compound.

Pharmacokinetics in Rat

The pharmacokinetics of certain compounds were determined followingintravenous (1 mg/kg) and oral (10 mg/kg) administration to male SpragueDawley rats. Dosing solution was prepared by mixing each compound with2% DMSO, 38% PEG-400 and 60% (0.9%) NaCl. Solutions were passed through0.2 μm filters prior to administration.

Following dosing and at appropriate time points, blood samples weretaken from a lateral tail vein and transferred into a tube pre-treatedwith EDTA. Blood samples were analysed for parent compound by LCMS andthe quantity of parent compound remaining determined. Non-compartmentalanalysis was applied to the data using WinNonlin™ software to determinethe pharmacokinetic parameters for each compound.

Biological Data Cellular In Vitro Enzyme Inhibition Data

The following compounds were tested using the cellular in vitro enzymeinhibition assays described above: AA-01 through AA-41, and BB-01through BB-15,

All of the compounds tested have an IC₅₀ for 11β-HSD1 of less than about10 μM. Many of the compounds have an IC₅₀ for 11β-HSD1 of less thanabout 1 μM. Many of the compounds have an IC₅₀ for 11β-HSD1 of less thanabout 500 nM.

Generally, the IC₅₀ ratio for 11β-HSD2 to 11β-HSD1 is at least aboutfive or greater, and in many cases ten or greater. For example, data forsome of the compounds is shown in the following table.

TABLE 1 In vitro Enzyme Inhibition Data IC₅₀ for IC₅₀ for Compound No.11β-HSD1 (HEK293) 11β-HSD2 (CHO) AA-01 208 nM  >10,000 nM AA-04 44nM >10,000 nM AA-06 21 nM >10,000 nM AA-08 10 nM >10,000 nM AA-12 99nM >10,000 nM AA-15 110 nM  >10,000 nM AA-18 104 nM  >10,000 nM AA-22 38nM >10,000 nM AA-30 15 nM >10,000 nM AA-33 19 nM >10,000 nM AA-36 42nM >10,000 nM AA-37 35 nM >10,000 nM BB-03 107 nM  >10,000 nM BB-08 114nM  >10,000 nM BB-11 638 nM  >10,000 nM

The following compounds have an IC₅₀ for 11β-HSD1 (HEK293) of less thanor equal to 500 nM (0.5 μM): AA-01, AA-02, AA-04, AA-05, AA-06, AA-07,AA-08, AA-09, AA-11, AA-12, AA-13, AA-14, AA-15, AA-16, AA-18, AA-21,AA-22, AA-23, AA-24, AA-25, AA-26, AA-27, AA-28, AA-29, AA-30, AA-31,AA-33, AA-34, AA-36, AA-37, AA-38, AA-40, BB-03, BB-04, BB-05, BB-07,BB-08, BB-09, BB-12, BB-14 and BB-15.

The following compounds have an IC₅₀ for 11β-HSD1 (HEK293) of more than500 nM (0.5 μM) and less than or equal to 1000 nM (1 μM): AA-03, AA-17,AA-32, AA-35, BB-01, BB-06, BB-10, BB-11 and BB-13.

The following compounds have an IC₅₀ for 11β-HSD1 (HEK293) of more than1000 nM (1.0 μM) and less than or equal to 10 μM: AA-10, AA-19, AA-20,AA-39, AA-41 and BB-02.

Human Liver Microsomal Stability Data

Data for some of the compounds are shown in the following table.

TABLE 2 Human Liver Microsomal Stability Data Compound No. % ParentRemaining at 30 min^((a)) AA-01 +++ AA-02 +++ AA-04 +++ AA-05 +++ AA-06+++ AA-07 +++ AA-08 ++ AA-09 +++ AA-15 ++ AA-16 + AA-17 +++ AA-18 ++AA-22 +++ AA-30 ++ AA-33 + AA-36 + AA-37 ++ BB-01 +++ BB-03 + BB-04 ++BB-05 ++ BB-06 +++ BB-07 + BB-08 ++ BB-13 +++ ^((a))Parent remainingafter 30 minutes: 0-30% +; 31-60% ++; 61-100% +++.

Compounds administered in vivo usually undergo metabolism, which occurspredominantly in the liver and to a lesser extent in the gut. Metabolismof compounds typically generates polar species that are cleared morerapidly from the body than the parent compound. One method of increasingthe concentration of a compound in the body is to slow down itsmetabolism in the liver (and gut) and hence reduce its clearance fromthe body. If a compound is administered orally and metabolism in the gutwall occurs, slowing the metabolism of a compound may also increase itsabsorption through the intestine leading to increased oralbioavailability. Increasing the metabolic stability and lowering theclearance of a compound is desirable since it helps to maintain levelsof the compound in the body and can prolong the duration of action ofthe compound.

Incubation of compounds with human liver microsomes is commonly used topredict the metabolism of compounds in vivo. Compounds with highmicrosomal stability are generally favoured since this often correlateswith an improved pharmacokinetic profile in vivo.

The majority of the PPPT compounds tested in human microsomal stabilityassays have high microsomal stability (61-100% parent compoundremaining). Fewer compounds have moderate microsomal stability (31-60%parent compound remaining) and fewer still have low microsomal stability(0-30%).

Rat Pharmacokinetic Data

Data for some of the compounds are shown in the following table:

TABLE 3 Rat Pharmacokinetic Data Compound No. % F^((b)) AA-01 +++ AA-02+++ AA-04 +++ AA-06 ++ AA-08 +++ AA-17 +++ ^((b))% Bioavailability (%F): 0-10% +; 11-30% ++; 31-100% +++

The bioavailability (% F) in rats of the majority of the PPPT compoundstested is greater than 30%.

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention.

REFERENCES

A number of publications are cited above in order to more fully describeand disclose the invention and the state of the art to which theinvention pertains. Full citations for these references are providedbelow. Each of these references is incorporated herein by reference inits entirety into the present disclosure, to the same extent as if eachindividual reference was specifically and individually indicated to beincorporated by reference.

-   Andrews, R. C., et al., 2003, “Effects of the 11beta-hydroxysteroid    dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men    with type 2 diabetes,” J. Clin. Endocrinol. Metab., Vol. 88, pp.    285-291.-   Christy, C., et al., 2003, “Glucocorticoid action in mouse aorta;    localisation of 11β-hydroxysteroid dehydrogenase type 2 and effects    on responses to glucocorticoids in vitro,” Hypertension, Vol. 42,    pp. 580-587.-   Cooper, M. S., et al., 2000, “Expression and functional consequences    of 11β-hydroxysteroid dehydrogenase activity in human bone,” Bone,    Vol. 27, pp. 375-381.-   Eckhardt et al., 2010, “Aryl- and Heteroarylcarbonyl derivatives of    substituted nortropanes, medicaments containing such compounds and    their use”, international patent publicaton number WO 2010/023161 A1    published 4 Mar. 2010.-   Hadoke, P. W. F., et al., 2001, “Endothelial cell dysfunction in    mice after transgenic knockout of type 2, but not type 1,    11β-hydroxysteroid dehydrogenase,” Circulation, Vol. 104, pp.    2832-2837.-   Kotelevtsev, Y. V., et al., 1997, “11β-Hydroxysteroid dehydrogenase    type 1 knockout mice show attenuated glucocorticoid inducible    responses and resist hyperglycaemia on obesity and stress,” Proc.    Natl. Acad. Sci., Vol. 94, pp. 14924-14929-   Masuzaki, H., et al., 2001, “A Transgenic Model of Visceral Obesity    and the Metabolic Syndrome,” Science, Vol. 294, pp. 2166-2170.-   Moisan, M. P., et al., 1990, “11 beta-hydroxysteroid dehydrogenase    bioactivity and messenger RNA expression in rat forebrain:    localization in hypothalamus, hippocampus, and cortex,”    Endocrinology, Vol. 127, pp. 1450-1455.-   Morton, N. M., et al., 2001, “Improved lipid and lipoprotein    profile, hepatic insulin sensitivity, and glucose tolerance in    11β-hydroxysteroid dehydrogenase type 1 null mice,” J. Biol. Chem.,    Vol. 276, pp. 41293-41300.-   Morton, N. M., et al., 2004, “Novel adipose tissue-mediated    resistance to diet-induced visceral obesity in 11β-hydroxysteroid    dehydrogenase type 1 deficient mice,” Diabetes, Vol. 53, pp.    931-938.-   Paterson, J. M., et al., 2004, “Metabolic syndrome without obesity:    hepatic overexpression of 11β-hydroxysteroid dehydrogenase type 1 in    transgenic mice,” Proc. Natl. Acad. Sci., Vol. 101, pp. 7088-7093).-   Rask, E., et al., 2001, “Tissue-specific dysregulation of cortisol    metabolism in human obesity,” J. Clin. Endocrinol. Metab., Vol. 86,    pp. 1418-1421.-   Rauz, S., et al., 2001, “Expression and putative role of 11    beta-hydroxysteroid dehydrogenase isozymes within the human eye,”    Investigative Opthalmology & Visual Science, Vol. 42, pp. 2037-2042.-   Sandeep, T. C., et al., 2004, “11β-hydroxysteroid dehydrogenase    inhibition improves cognitive function in healthy elderly men and    type 2 diabetics,” Proc. Natl. Acad. Sci., Vol. 101, pp. 6734-6739.-   Seckl, J. R., Walker, B. R., 2001, “113-Hydroxysteroid dehydrogenase    type 1-a tissue-specific amplifier of glucocorticoid action,”    Endocrinology, Vol. 142, pp. 1371-1376.-   Small, G. R., et al., 2005, “Preventing local regeneration of    glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances    angiogenesis,” Proc. Natl. Acad. Sci., Vol. 102, pp. 12165-12170.-   Walker, B. R., et al., 1991, “11β-Hydroxysteroid dehydrogenase in    vascular smooth muscle and heart: implications for cardiovascular    responses to glucocorticoids,” Endocrinology, Vol. 129, pp.    3305-3312.-   Walker, B. R., et al., 1995, “Carbenoxolone increases hepatic    insulin sensitivity in man: a novel role for 11-oxosteroid reductase    in enhancing glucocorticoid receptor activation,” J. Clin.    Endocrinol. Metab., Vol. 80, pp. 3155-3139.-   Yau, J. L. W., et al., 2001, “Lack of tissue glucocorticoid    reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout    mice ameliorates age-related learning impairments,” Proc. Natl.    Acad. Sci., Vol. 98, pp. 4716-4721.

1-124. (canceled)
 125. A compound of the following formula, or apharmaceutically acceptable salt thereof:

wherein: —W is —Y; —Y is independently —Y¹, —Y², —Y³, —Y⁴, or —Y⁵; —Y¹is —OH; —Y² is independently —Y^(2A); Y^(2B); or Y^(2C); —Y³ isindependently —Y^(3A), —Y^(3B), or —Y^(3C); —Y⁴ is independently —F,—Cl, —Br, or —I; —Y⁵ is —CN; wherein: —Y^(2A) is —OR^(YA); —Y^(2B) is—OR^(YB); —Y^(2C) is —OR^(YC); —Y^(3A) is —R^(YA); —Y^(3B) is —R^(YB);—Y^(3C) is —R^(YC); wherein: each —R^(YA) is saturated aliphaticC₁₋₆alkyl; each —R^(YB) is saturated aliphatic halo-C₁₋₆alkyl; each—R^(YC) is saturated aliphatic hydroxy-C₁₋₆alkyl; and wherein: each of-J¹, -J², -J³, and -J⁴ is —H; or each of -J² and -J⁴ is —H; and -J¹ and-J³ taken together form —CH₂— or —CH₂CH₂—; or each of -J¹ and -J³ is —H;and -J² and -J⁴ taken together form —CH₂— or —CH₂CH₂—; or each of -J²and -J³ is —H; and -J¹ and -J⁴ taken together form —CH₂— or —CH₂CH₂—;and wherein: —R^(N) is independently —H or —R^(NN); —R^(NN) is saturatedaliphatic C₁₋₆alkyl; and wherein: —R^(B1) is independently —H or—R^(BB); —R^(B2) is independently —H or —R^(BB); wherein: each —R^(BB)is independently —R^(BB1), —R^(BB2) or —R^(BB3); wherein: each —R^(BB1)is saturated aliphatic C₁₋₆alkyl, and is optionally substituted with oneor more substituents selected from —F, —OH, —OR^(BBB), —OCH₂F, —OCHF₂,—OCF₃, —NH₂, —NHR^(BBB), and —NR^(BB) ₂; wherein each —R^(BBB) issaturated aliphatic C₁₋₄alkyl; each —R^(BB2) is independently —F, —Cl,—Br, or —I; each —R^(BB3) is —CN; and wherein: n is independently 0, 1,2, 3, 4, or 5; each —R^(F) is independently —R^(Z), —F, —Cl, —Br, —I,—CF₃, —OH, —OR^(Z), —OCF₃, —SR^(Z), —S(═O)₂R^(Z), or —CN; and each—R^(Z) is aturated aliphatic C₁₋₆alkyl, and is optionally substitutedwith one or more substituents selected from —F, —Cl, —OH, —OR^(ZZ),—OCH₂F, —OCHF₂, and —OCF₃; wherein each —R^(ZZ) is saturated aliphaticC₁₋₄alkyl.
 126. A compound according to claim 125, wherein: —Y¹ is —OH;—Y² is —Y^(2A); —Y³ is —Y^(3A) or —Y^(3C); —Y⁴ is —F; and —Y⁵ is —CN;—Y^(2A) is —OR^(YA); —Y^(3A) is —R^(YA); —Y^(3C) is —R^(YC); each—R^(YA) is -Me; and —R^(YC) is —CH₂OH.
 127. A compound according toclaim 126, wherein —Y is —Y¹ or —Y⁴.
 128. A compound according to claim126, wherein: each of -J¹, -J², -J³, and -J⁴ is —H; or each of -J² and-J⁴ is —H, and -J¹ and -J³ taken together form —CH₂CH₂—; or each of -J¹and -J³ is —H; and -J² and -J⁴ taken together form —CH₂CH₂—.
 129. Acompound according to claim 127, wherein: each of -J¹, -J², -J³, and -J⁴is —H; or each of -J² and -J⁴ is —H, and -J¹ and -J³ taken together form—CH₂CH₂—; or each of -J¹ and -J³ is —H; and -J² and -J⁴ taken togetherform —CH₂CH₂—.
 130. A compound according to claim 126, wherein: each of-J¹, -J², -J³ and -J⁴ is —H.
 131. A compound according to claim 127,wherein: each of -J¹, -J², -J³, and -J⁴ is —H.
 132. A compound accordingto claim 126, wherein: —R^(NN) is saturated aliphatic C₁₋₄alkyl; each—R^(BB1) is unsubstituted saturated aliphatic C₁₋₄alkyl; and each—R^(BB2) is —F or —Cl.
 133. A compound according to claim 132, whereineach —R^(BB) is —R^(BB1).
 134. A compound according to claim 127,wherein: —R^(NN) is saturated aliphatic C₁₋₄alkyl; each —R^(BB1) isunsubstituted saturated aliphatic C₁₋₄alkyl; and each —R^(BB2) is —F or—Cl.
 135. A compound according to claim 134, wherein each —R^(BB) is—R^(BB1).
 136. A compound according to claim 129, wherein: —R^(NN) issaturated aliphatic C₁₋₄alkyl; each —R^(BB1) is unsubstituted saturatedaliphatic C₁₋₄alkyl; and each —R^(BB2) is —F or —Cl.
 137. A compoundaccording to claim 136, wherein each —R^(BB) is —R^(BB1).
 138. Acompound according to claim 126, wherein: —R^(N) is —H; —R^(B1) is —H;and —R^(B2) is —H.
 139. A compound according to claim 127, wherein:—R^(N) is —H; —R^(B1) is —H; and R^(B2) is H.
 140. A compound accordingto claim 129, wherein: —R^(N) is —H; —R^(B1) is —H; and —R^(B2) is —H.141. A compound according to claim 126, wherein: n is independently 0,1, 2, or 3; and each —R^(F) is independently —F, —Cl, -Me, -Et, —OH,—OMe, —OEt, —CF₃, —OCF₃, or —CN.
 142. A compound according to claim 126,wherein: n is independently 0, 1, or 2; and each —R^(F) is independently—F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.
 143. A compoundaccording to claim 127, wherein: n is independently 0, 1, or 2; and each—R^(F) is independently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃,or —CN.
 144. A compound according to claim 129, wherein: n isindependently 0, 1, or 2; and each —R^(F) is independently —F, —Cl, -Me,-Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.
 145. A compound according toclaim 133, wherein: n is independently 0, 1, or 2; and each —R^(F) isindependently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.146. A compound according to claim 135, wherein: n is independently 0,1, or 2; and each —R^(F) is independently —F, —Cl, -Me, -Et, —OH, —OMe,—OEt, —CF₃, —OCF₃, or —CN.
 147. A compound according to claim 137,wherein: n is independently 0, 1, or 2; and each —R^(F) is independently—F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.
 148. A compoundaccording to claim 138, wherein: n is independently 0, 1, or 2; and each—R^(F) is independently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃,or —CN.
 149. A compound according to claim 139, wherein: n isindependently 0, 1, or 2; and each —R^(F) is independently —F, —Cl, -Me,-Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.
 150. A compound according toclaim 140, wherein: n is independently 0, 1, or 2; and each —R^(F) isindependently —F, —Cl, -Me, -Et, —OH, —OMe, —OEt, —CF₃, —OCF₃, or —CN.151. A compound according to claim 125, selected from compounds of thefollowing formulae or a pharmaceutically acceptable salt thereof:


152. A pharmaceutical composition comprising a compound according toclaim 125 and a pharmaceutically acceptable carrier or diluent.
 153. Amethod of preparing a pharmaceutical composition comprising the step ofadmixing a compound according to claim 125 and a pharmaceuticallyacceptable carrier or diluent.
 154. A method of inhibiting11β-hydroxysteroid dehydrogenase type 1 function in a cell, in vitro,comprising contacting the cell with an effective amount of a compoundaccording to claim
 125. 155. A method of treatment or prevention of adisorder of the human or animal body that is ameliorated by theinhibition of 11β-hydroxysteroid dehydrogenase type 1 comprisingadministering to a subject in need of treatment atherapeutically-effective amount of a compound according to claim 125.156. A method according to claim 154, wherein the treatment is treatmentor prevention of: (1) Cushing's syndrome; (2) type 2 diabetes andimpaired glucose tolerance; (3) insulin resistance syndromes such asmyotonic dystrophy, Prader Willi, lipodystrophies, polycystic ovarysyndrome, gastrointestinal diabetes, etc; (4) obesity and beingoverweight; (5) lipid disorders including dyslipidaemia; (6)atherosclerosis and its sequelae, including myocardial infarction andperipheral vascular disease; (7) Metabolic Syndrome; (8)steatohepatitis/fatty liver and non-alcoholic fatty liver disease; (9)cognitive impairment in type 2 diabetes, glucose intolerance and ageing,and in psychotic disorders and pre-schizophrenia; (10) dementias such asAlzheimer's disease, multi-infarct dementia, dementia with Lewy bodies,fronto-temporal dementia (including Picks disease), progressivesupranuclear palsy, Korsakoff's syndrome, Binswanger's disease,HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiplesclerosis, motor neurone disease, Parkinson's disease, Huntington'sdisease, Niemann-Pick disease type C, normal pressure hydrocephalus, andDown's syndrome; (11) mild cognitive impairment (cognitive impairment,no dementia); (12) 3-cell dysfunction in pancreatic disease; (13)glaucoma; (14) anxiety; (15) depression and other affective disorders;typical (melancholic) and atypical depression; dysthymia; post-partumdepression; bipolar affective disorder; drug-induced affectivedisorders; anxiety; posttraumatic stress disorder; panic; phobias; (16)delirium and acute confusional state; (17) inflammatory disease; (18)osteoporosis; (19) myocardial infarction, for example, to prevent leftventricular dysfunction after myocardial infarction; or (20) stroke, forexample, to limit ischaemic neuronal loss after cardiovascular accident;or (1) hyperglycaemia; (2) glucose intolerance and impaired glucosetolerance; (3) insulin resistance; (4) hyperlipidaemia; (5)hypertriglyceridaemia; (6) hypercholesterolaemia; (7) low HDL levels;(8) high LDL levels; (9) vascular restenosis; (10) abdominal obesity;(11) neurodegenerative disease; (12) retinopathy; (13) neuropathy; (14)hypertension; or (15) other diseases where insulin resistance is acomponent; or an adverse effect of glucocorticoids used to treatinflammatory diseases, such as asthma, chronic obstructive pulmonarydisease, skin diseases, rheumatoid arthritis and other arthropathies,inflammatory bowel disease, and giant cell arthritis/polymyalgiarheumatica; or metabolic syndrome, which includes disorders such as type2 diabetes and obesity, and associated disorders including insulinresistance, hypertension, lipid disorders and cardiovascular disorderssuch as ischaemic (coronary) heart disease; or a CNS disorder such asmild cognitive impairment and early dementia, including Alzheimer'sdisease.